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Oculodentodigital Dysplasia: A Case Report and Major Review of the Eye and Ocular Adnexa Features of 295 Reported Cases.

1. Introduction

Oculodentodigital dysplasia (ODDD, OMIM #164200) is a rare disorder mainly characterized by abnormal craniofacial, dental, ocular, and digital development. The autosomal dominant form has been the most frequently reported inheritance pattern, although a few cases of autosomal recessive inheritance have been described [1-3]. Craniofacial abnormalities may include microcephaly, prominent columella, and underdeveloped nasal alae [2-4]. Dental abnormalities, such as hypoplastic enamel, small teeth, and premature loss of teeth, are often present [2-4]. Digit abnormalities may include syndactyly, camptodactyly, and midphalangeal hypoplasia [2-4]. Ophthalmic manifestations are common, such as microcornea and microphthalmia, and may involve a wide spectrum of eye and ocular adnexa structures, although previous analyses of prior cases show that full ocular physical exams were not performed on all patients [3, 5].

The gap junction protein alpha 1 (GJA1) gene codes for connexin-43, which is a protein that assists in the transmembrane transport of molecules through gap junctions, and mutations in the GJA1 may cause an alteration of the channel conduction properties [1-3, 6]. We report a case of an 8-month-old female patient with an identified GJA1 mutation and common clinical features associated with ODDD. This patient had an omphalocele at birth, which has not been reported in previous cases. Her eye features included microphthalmia, microcornea, narrow palpebral fissures, blonde fundus, deep anterior chambers, hyperopia, and epiphora in both eyes secondary to bilateral nasolacrimal duct obstructions. We conducted an extensive literature review to summarize the eye features in patients with ODDD reported to date.

2. Case Report

The patient, an 8-month-old female, was born to a nonconsanguineous couple from a healthy 37-year-old mother of Native American descent and a healthy 30-year-old father of German and Irish descent. Family history is notable for an older sibling with cleft palate, paternal uncle with autism, paternal second cousin with congenital heart defect, and distant paternal great-great uncle with Down syndrome and webbed/fused 4th and 5th digits of one hand. A normal pregnancy was noted until the second trimester when an omphalocele was detected on ultrasound. A subsequent ultrasound revealed possible syndactyly of the hands. The patient was born at 39 weeks by vaginal delivery with induction. The birth weight was 3.552 kg (75th percentile), birth length was 50 cm (68th percentile), and birth head circumference was 34.5 cm (70th percentile). Apgar scores were 9 at both one minute and five minutes.

Multiple congenital anomalies noted at birth included an omphalocele that measured 4 cm at base and 3.5 cm across with intestines present in the sac, but no liver. The patient had a normocephalic head with sparse wispy hair, a small nose with hypoplastic alae, a prominent columella, smallappearing palpebral fissures, a small cornea, microphthalmia, a wide anterior fontanelle, and retrognathia (Figure 1). Syndactyly of digits 4 and 5 and webbing of digits 3 and 4 of the right (Figure 2) and left hands were present. Cardiac echocardiogram on the day of birth showed the presence of a mild patent ductus arteriosus, mild patent foramen ovale, and a normal aorta. Feeding difficulties were exacerbated by the presence of the omphalocele; surgical correction was performed on day 2 of life.

An ophthalmologic assessment at 4 months of age was notable for deep anterior chambers, bilateral nasolacrimal duct obstruction, microphthalmia, small 8 mm corneas, a blonde fundus, and moderate hyperopia in both eyes.

At her last examination at 8 months of age, the patient continues to have poor feeding with self-limiting volumes but has improved weight gain. The patient is at the 9th percentile for weight and 12th percentile for length. Cognitive and motor developments are delayed.

Sequencing of the GJA1 gene (transcript number: NM_ 000165.3) from patient genomic DNA revealed a heterozygous missense mutation in the GJA1 gene: c.65G>A (p.G22E). Deletion/duplication analysis of the GJA1 gene using the aCGH test was negative.

3. Methods

We performed a systematic review of the literature to summarize the ocular findings in individuals with ODDD. A PubMed/Medline search of "oculodentodigital syndrome" led us to find a total of 177 articles. No articles were excluded based on the year published. We reviewed the references to identify other articles that did not appear in our original search. 91 articles describing patients with a description consistent with the clinical syndrome, either with or without molecular confirmation of GJA1 pathogenic variants, were included. Within these selected articles, we identified 295 cases of ODDD with 73 different GJA1 mutations, including those that exhibited features of ODDD in the absence of molecular confirmation. Such individuals were either clinically diagnosed or were relatives of individuals with molecularly confirmed GJA1 pathogenic variants. Twelve reported that GJA1 gene coding alterations were omitted due to insufficient clinical information and data reported and are listed in Table 1 [3, 6].

4. Discussion

Oculodentodigital dysplasia (ODDD) is a rare congenital disorder manifested with developmental anomalies of the eyes, face, dentition, heart, skeletal system, and digits. The syndrome appears to be more common in Caucasian populations with an equal sex ratio [3]. Heterozygous mutation of the GJA1 gene located at chromosome 6q22.31 has been identified as the most common mutation resulting in ODDD [2, 3]. However, a compound heterozygous individual with missense mutations demonstrated mutations in the GJA1 gene (p.V41L) and the GJB2 gene (p.R127H), which encode for connexin-43 and connexin-26, respectively, and has been reported and classified as having overlapping features of Clouston syndrome and ODDD [3, 7].

In addition to the classic phenotypic features of the syndrome, a wide variety of additional physical manifestations have been observed. Ocular findings of microphthalmia and microcornea have been observed commonly in previous cases [2-4]. Craniofacial anomalies of microcephaly, poor hair growth, hypoplastic nasal alae, and prominent columella have been reported previously [2-4]. Bilateral syndactyly of the 4th and 5th digits is common [2, 3].

A systematic review of the published cases to date (ranging from 1963 to 2019) revealed 91 literature reports of 295 individuals with ODDD [1-91]. Table 2 [1-91] summarizes the sex distribution across all reviewed reports of ODDD. Patients with ODDD present with an approximately equal sex distribution (47% male and 53% female). Of the 295 individuals reported, 32 were clinically diagnosed with ODDD without molecular confirmation, 98 presented with features of ODDD and had a known relative with molecular confirmation of a GJA1 pathogenic variant, and 165 individuals had a molecularly confirmed GJA1 pathogenic variant.

There were 73 different GJA1 mutations identified from the 165 individuals that had a molecularly confirmed GJA1 pathogenic variant. Table 3 [1-3, 5-71, 92] summarizes the number of patients with each mutation. Patients with confirmed pathogenic variants and their relatives with no molecular confirmation but with features of ODDD were grouped separately. These two groups comprised 263 of the patients included in this study.

The eye features of all 295 patients are summarized in Table 4 [1-91]. The most common ophthalmic manifestations reported were microcornea (n = 111), microphthalmia (n =110), short palpebral fissures (n = 56), and glaucoma (n = 51,4 closed-angle and 1 open-angle).

Twenty-three patients presented with refractive error, of which isolated myopia was the most frequently noted (n = 14), followed by isolated hyperopia (n = 6), anisometropia (n = 2), and astigmatism (n = 1). Forty patients presented with eye movement disorders, with strabismus (n = 27, 9 esotropic, 1 exotropic) being the most common, followed

by nystagmus (n = 8), amblyopia (n = 3), Duane syndrome (n = 2), and Brown syndrome (n = 1). Note that 1 patient had both nystagmus and esotropia [71]. Other common findings included epicanthus (n = 36), hypotelorism (n = 24), hypertelorism (n = 22), madarosis (n = 19), cataracts (n = 17), persistent pupillary membranes (n =13), shallow anterior chambers (n = 12), pale/atrophic irides (n = 11), telecanthus (n = 11), and uveitis (n = 10).

A variety of abnormal findings for the retina and optic disc were noted (n = 18), with dysplasia of the retina/fundus (n = 3) and pale/atrophic optic discs (n = 3) being the most common documented findings.

Of the individuals with molecularly confirmed mutations, the most common mutations present were c.605G>A (p.R202H) (11%; with 1 patient also having a c.717G>A synonymous mutation), c.389T>C (p.I130T) (10%), and c.119C>T (p.A40V) (10%). Table 5 [2, 3, 12, 30, 40, 41, 66, 67, 92] summarizes the eye features present in the patients with these mutations.

Less common features of the phenotype observed in our presented case were also reported in other cases as well. These include nasolacrimal duct abnormalities (n = 2), pale/atrophic retina/fundus (n = 2), and deep anterior chambers (n = 2). Additionally, including this study, the three patients with the p.G22E mutation have the following findings: microphthalmia (n = 3), cataracts (n =1), microcornea (n = 2), blonde fundus (n =1), persistent pupillary membrane (n = 1), deep anterior chamber (n = 1), hyperopia (n = 1), strabismus (n = 2, 1 esotropic), amblyopia (n = 1), glaucoma (n = 1), short palpebral fissures (n = 1), nasolacrimal duct abnormalities (n = 1), and epicanthus (n = 1) [2, 3, 21, 22].

Some unique genotype-phenotype correlations were noted upon further analysis. Three patients presented with eccentric pupils, but only 2 of these patients were reported with an associated mutation. Both mutations (p.Q49dup and p.Q49P) seem to affect the same amino acid in connexin-43 [3, 61, 72]. Additionally, uveitis was reported in 10 patients, 9 of which were associated with similar mutations. Eight of these patients were within the same study and had the p.H194P mutation, another patient had no molecular confirmation of a GJA1 mutation, and the other patient was reported with a missense mutation on exon 2 [4, 9, 10, 27, 28]. However, since the majority of these patients were reported within the same study, the apparent genotype-phenotype correlation of p.H194P and uveitis might be due to underreporting of uveitis from other sources with different pathogenic variants or may be due to other factors of the family not identified within the study.

Further analysis of the genotype-phenotype correlation was conducted by pairing the phenotypic manifestations of each mutation with the corresponding defects in the connexin-43 domains. The domains were defined by the amino acid ranges provided on UniProt (P17302-CXA1_ HUMAN) [93]. Table 6 [1-3, 5-71, 92, 93] provides a summary of the phenotypes associated with mutations from each domain.

The domains most commonly affected by GJA1 mutations are the extracellular-1 loop and the cytoplasmic-1 loop of connexin-43, accounting for 19 and 20 mutations, respectively. Disruptions in the extracellular-1 loop presented primarily as microphthalmia (n = 32) and microcornea (n = 30). A similar pattern can be seen in the cytoplasmic-1 loop, as the most common presentations were microphthalmia (n = 20) and microcornea (n =18). Other clinical findings, however, may be able to distinguish mutations resulting from these domains. The next most common findings associated with mutations in the extracellular-1 loop were glaucoma (n =15) and hypertelorism (n =11), as opposed to short palpebral fissures (n = 14) and hypotelorism (n = 14) for the cytoplasmic-1 loop.

Mutations affecting the cytoplasmic N-terminus and the transmembrane-1 domain shared similar features to the ones in the extracellular-1 and cytoplasmic-1 domains, as microphthalmia and microcornea were the most common clinical findings. However, the mutations in the cytoplasmic N-terminus and transmembrane-1 domain presented with microcornea (n =17 and n = 21, respectively) more frequently than microphthalmia (n = 5 and n = 14, respectively). The opposite pattern is true for the extracellular-1 and cytoplasmic-1 domains.

The mutations in the extracellular-2 loop demonstrate a different phenotypic pattern, as microphthalmia (n = 14) occurs the most frequently, while microcornea is less frequent (n = 4). Mutations in the transmembrane-2 domain also display a unique pattern, with hypertelorism (n = 5) being the most frequent clinical finding. Other domains listed in Table 6 also demonstrate some unique clinical patterns, but this may be due to variability from the small number of samples. The patterns mentioned previously, however, still provide insight into the role of different connexin-43 domains in providing phenotypic variability among patients with ODDD.

In conclusion, this report provides a comprehensive review of the eye and ocular adnexa abnormalities that are currently known to be associated with the ODDD phenotype. Limitations of this report include the possibility of an incomplete ophthalmologic evaluation and/or lack of reporting of eye features in all of the evaluated case reports or misdiagnosis in the individuals with the ODDD phenotype without molecular confirmation. As such, it is possible that the reported common eye features within this summary may be over or underrepresented. Ophthalmic manifestations are commonly associated within the phenotype, and a wide spectrum of eye and ocular adnexa structures may be affected. The rarity of this condition provides further incentive to further investigate the phenotype.

https://doi.org/10.1155/2020/6535974

Consent

Consent has been obtained.

Conflicts of Interest

Virang Kumar and Arti Pandya declare that they have no conflicts of interest. Natario L. Couser, MD, MS, is a principal investigator at the Virginia Commonwealth University site of Retrophin, Inc., and book editor in Elsevier.

Supplementary Materials

Supplementary Material 1: all GJA1 mutations with associated eye and ocular adnexa features. This dataset groups patients with ODDD by GJA1 mutation and reports the associated eye and ocular adnexa features. (Supplementary Materials)

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[88] H. S. Sugar, "Oculodentodigital dysplasia syndrome with angle-closure glaucoma," American Journal of Ophthalmology, vol. 86, no. 1, pp. 36-38, 1978.

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Virang Kumar [ID], (1) Natario L. Couser [ID], (2,3,4) and Arti Pandya (5)

(1) Virginia Commonwealth University School of Medicine, Richmond, VA, USA

(2) Department of Ophthalmology, Virginia Commonwealth University School of Medicine, Richmond, VA, USA

(3) Department of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA, USA

(4) Department of Pediatrics, Virginia Commonwealth University School of Medicine, Richmond, VA, USA

(5) Department of Pediatrics, Division of Genetics and Metabolism, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

Correspondence should be addressed to Virang Kumar; kumarvk@vcu.edu

Received 22 September 2019; Accepted 23 March 2020; Published 6 April 2020

Academic Editor: Sandra M. Johnson

Caption: FIGURE 1: Facial photograph of a patient with oculodentodigital dysplasia; note the beaked nose with hypoplastic alae and prominent columella, microphthalmia, microcornea, small palpebral fissures, retrognathia.

Caption: FIGURE 2: Complete syndactyly of the 4th and 5th digits of the right hand.
TABLE 1: GJA1 variants without clinical information.

Sources                       GJA1 variant       Cases

                          Nucleotide   Protein

Paznekas et al. [3]         c.7G>A      p.D3N      1
Paznekas et al. [3]        c.64G>A     p.G22R      1
Paznekas et al. [3];       c.79T>C     p.S27P      1
  Richardson et al. [6]
Paznekas et al. [3]        c.163A>G    p.N55D      1
Paznekas et al. [3]        c.174A>C    p.Q58H      1
Paznekas et al. [3]        c.175C>G    p.P59A      1
Paznekas et al. [3]        c.221A>T    p.H74L      1
Paznekas et al. [3]        c.428G>A    p.G143D     1
Paznekas et al. [3]        c.430A>G    p.K144E     1
Paznekas et al. [3]        c.434T>G    p.V145G     1
Paznekas et al. [3]        c.442C>G    p.R148G     1
Paznekas et al. [3]        c.578C>T    p.P193L     1

TABLE 2: Summary of sex distribution.

                                   Males     Females     Total

Individuals with clinical       14    45%   18    56%     32
  diagnosis of ODDD (with no
  molecular confirmation)
Untested individuals with       52    53%   46    47%     98
  both ODDD phenotype and
  known relative with
  molecular confirmation
Individuals with a molecular    72    44%   93    56%     165
  confirmed GJA1 pathogenic
  variant
Totals                          138   47%   157   53%     295

TABLE 3: Reported GJA1 mutations and sex distribution in ODDD.

Sources                      Multiple      GJA1 mutation
                            mutations?
                                             Nucleotide

Cavusoglu et al. 2019           No         c.168_169insT
Aminabadi et al. 2009           No              N/A
  & Aminabadi et
  al. 2010
Dwarakanathan et                No            c.75G>T
  al. 2015 & Furuta
  et al. 2012
Quick and Dobersen 2014;       Yes            c.605G>A
  National Center for                         c.717G>A
  Biotechnology
  Information 2020
Paznekas et al. 2003 &          No            c.605G>A
  Paznekas et al. 2009
Jamsheer et al. 2010           Yes        c.301C>T c.6delT
Jamsheer et al. 2010            No            c.301C>T
Paznekas et al. 2009;           No            c.97C>T
  Joss et al. 2008; &
  Richardson et
  al. 2006
Paznekas et al. 2009;           No            c.93T>C
  Richardson et al.
  2004; Paznekas et
  al. 2003; & Gladwin
  et al. 1997
Wang et al. 2019                No            c.91A>T
Paznekas et al. 2009            No        c.780_ 781delTG
  & van Steensel et
  al. 2005
Paznekas et al. 2009;           No            c.68A>C
  Paznekas et al.
  2003; & Gorlin et
  al. 1963
Dwarakanathan et                No        c.689_ 690delAT
  al. 2015; Paznekas
  et al. 2009; &
  Vreeburg et al. 2007
This study; Gumus               No            c.65G>A
  2018; Paznekas et
  al. 2009; Paznekas
  et al. 2003; &
  Traboulsi and
  Parks 1990
Wiest et al. 2006               No            c.659C>A
Paznekas et al. 2009;           No            c.646G>T
  Paznekas et al.
  2003; & Norton et
  al. 1995
Park et al. 2017;               No            c.61G>A
  Paznekas et al.
  2009; & Paznekas
  et al. 2003
Brice et al. 2013               No            c.617A>G
Paznekas et al. 2009            No            c.602C>T
Paznekas et al. 2009            No             c.5G>T
  & de la Parra et
  al. 2007
Vitiello et al. 2005            No            c.581A>C
  & Vingolo et
  al. 1994
Paznekas et al.                 No            c.52T>C
  2009; Paznekas et
  al. 2003; & Judisch
  et al. 1979
Paznekas et al. 2009            No            c.50A>C
  & Paznekas et
  al. 2003
Paznekas et al. 2009            No        c.504_ 506delCTT

  & Debeer et
  al. 2005
Wiest et al. 2006 &             No            c.461C>A
  Thomsen et
  al. 1998
Paznekas et al. 2009            No            c.460A>G
  & van Es et
  al. 2007
Paznekas et al.                 No            c.443G>A
  2009; Richardson
  et al. 2004;
  Paznekas et al.
  2003; Gladwin et
  al. 1997; &
Schrander-Stumpel               No            c.442C>T
  et al. 1993
  Tafdelen et
  al. 2018
Paznekas et al.                 No            c.440Y>C
  2009; Debeer et
  al. 2005; &
  Spaepen et
  al. 1991
Paznekas et                     No            c.427G>A
  al. 2009;
  Richardson et al.
  2004; & Brueton
  et al. 1990
Orosz et al. 2018               No            c.413G>A
Paznekas et al.                 No            c.412G>C
  2009; Paznekas et
  al. 2003; &
  Shapiro et al. 1997
Kogame et al. 2014              No            c.412G>A
Paznekas et                     No            c.402G>T
  al. 2009;
  Richardson et
  al. 2004; Paznekas
  et al. 2003; &
  Gladwin et al. 1997
Paznekas et al. 2009            No            c.400A>G
  & Paznekas et
  al. 2003
Nishat et al. 2012;             No            c.389T>C
  Paznekas et al. 2009;
  Paznekas et al. 2003;
  & Amador et al. 2008
Paznekas et al. 2009;           No            c.338T>C
  Musa et al. 2008;
  Wiest et al. 2006; &
  Loddenkemper et
  al. 2002
Paznekas et al. 2009            No            c.330G>C
  & Debeer et al. 2005
Paznekas et al. 2009            No            c.32T>C
  & Kelly et al. 2006
Gabriel et al. 2011             No            c.31C>T
  & Jamsheer et
  al. 2009
Porntaveetus et                 No            c.31C>A
  al. 2017
Jamsheer et al. 2014            No            c.317T>G
Paznekas et al. 2009            No            c.317T>C
  & Nivelon-Chevallier
  et al. 1981
Paznekas et al. 2009            No            c.306G>C
  & Paznekas et al. 2003
Paznekas et al. 2009;           No            c.293A>G
  Paznekas et al. 2003;
  & Wooldridge et
  al. 1977
Paznekas et al. 2009            No            c.287T>C
Wiest et al. 2006               No            c.287T>A
Paznekas et al. 2009            No            c.286G>A
  & Kjaer et al. 2004
Paznekas et al. 2009            No            c.284A>G
  & Honkaniemi et
  al. 2005
Paznekas et al. 2009;           No            c.268C>G
  Paznekas et al. 2003;
  & Opjordsmoen and
  Nyberg-Hansen 1980
Jamsheer et al. 2014            No            c.257C>A
Pizzuti et al. 2004             No            c.227G>A
Izumi et al. 2013               No            c.226C>T
Paznekas et al. 2009;           No            c.226C>A
  Paznekas et al. 2003;
  & Stanislaw et
  al. 1998
Choi et al. 2018                No            c.221A>C
Paznekas et al. 2009;           No            c.206C>A
  Richardson et al.
  2004; Paznekas et
  al. 2003; & Gladwin
  et al. 1997
Paznekas et al. 2009 &          No            c.176C>A
  Vasconcellos et
  al. 2005
Paznekas et al. 2009            No        c.145_ 147dupCAG
Pazenkas et al. 2009;           No        c.154_ 156dupTTT
  Paznekas et al. 2003;
  Weintraub et al.
  1975; & Gellis and
  Feingold 1974
Hadjichristou et                No            c.146A>C
  al. 2017 & Paznekas
  et al. 2009
Izumi et al. 2013               No            c.145C>G
Paznekas et al. 2009            No            c.145C>A
  & Paznekas et al. 2003
Amano et al. 2012;              No            c.142G>A
  Feller et al. 2008;
  Paznekas et al. 2009;
  & Itro et al. 2005
Jamsheer et al. 2014            No            c.139G>C
Tumminelli et al. 2016          No            c.125G>C
Gabriel et al. 2011             No          c.120delGGTT
                                              GAGTCAGC
Paznekas et al. 2009           Yes            c.121G>C
  & Kellermayer et          (compound           N/A
  al. 2005                 heterozygous
                            with GJB2
                            mutation)
Park et al. 2019;               No            c.119C>T
  Hayashi et al.
  2014; Paznekas et
  al. 2009; Debeer et
  al. 2005; & Paznekas
  et al. 2003
Wittlieb-Weber et               No           c. 175C>T
  al. 2015
Attig et al. 2016               No        c.396_ 398delAAA
Paznekas et al. 2009            No            c.19T>G
Himi et al. 2009                No            c.13A>T
Pace et al. 2019                No            c.287T>G
                                No            c.77T>C
Totals

Sources                                GJA1 mutation

                               Protein         Unspecified

Cavusoglu et al. 2019        p.Q57SfsTer6          N/A
Aminabadi et al. 2009            N/A            Missense
  & Aminabadi et                                mutation
  al. 2010                                       exon 2
                                              (unspecified)
Dwarakanathan et                p.W25C             N/A
  al. 2015 & Furuta
  et al. 2012
Quick and Dobersen 2014;       p.R202H             N/A
  National Center for          p.R239R
  Biotechnology
  Information 2020
Paznekas et al. 2003 &         p.R202H             N/A
  Paznekas et al. 2009
Jamsheer et al. 2010       p.RlOIX p.G2fsX7        N/A
Jamsheer et al. 2010           p.RlOIX             N/A
Paznekas et al. 2009;          p.R33X*             N/A
  Joss et al. 2008; &
  Richardson et
  al. 2006
Paznekas et al. 2009;           p.I31M             N/A
  Richardson et al.
  2004; Paznekas et
  al. 2003; & Gladwin
  et al. 1997
Wang et al. 2019               p.I311P             N/A
Paznekas et al. 2009         p.C260fsX306          N/A
  & van Steensel et
  al. 2005
Paznekas et al. 2009;           p.K23T             N/A
  Paznekas et al.
  2003; & Gorlin et
  al. 1963
Dwarakanathan et             p.Y230fsX236          N/A
  al. 2015; Paznekas
  et al. 2009; &
  Vreeburg et al. 2007
This study; Gumus               p.G22E             N/A
  2018; Paznekas et
  al. 2009; Paznekas
  et al. 2003; &
  Traboulsi and
  Parks 1990
Wiest et al. 2006              p.S220Y             N/A
Paznekas et al. 2009;          p.V216L             N/A
  Paznekas et al.
  2003; & Norton et
  al. 1995
Park et al. 2017;               p.G21R             N/A
  Paznekas et al.
  2009; & Paznekas
  et al. 2003
Brice et al. 2013              p.K206R             N/A
Paznekas et al. 2009           p.S201F             N/A
Paznekas et al. 2009            p.G2V              N/A
  & de la Parra et
  al. 2007
Vitiello et al. 2005           P.H194P*            N/A
  & Vingolo et
  al. 1994
Paznekas et al.                 p.S18P             N/A
  2009; Paznekas et
  al. 2003; & Judisch
  et al. 1979
Paznekas et al. 2009            p.Y17S             N/A
  & Paznekas et
  al. 2003
Paznekas et al. 2009          p.F169del            N/A
  & Debeer et
  al. 2005
Wiest et al. 2006 &            p.T154N             N/A
  Thomsen et
  al. 1998
Paznekas et al. 2009           P.T154A*            N/A
  & van Es et
  al. 2007
Paznekas et al.                p.R148Q             N/A
  2009; Richardson
  et al. 2004;
  Paznekas et al.
  2003; Gladwin et
  al. 1997; &
Schrander-Stumpel             p.R148Ter            N/A
  et al. 1993
  Tafdelen et
  al. 2018
Paznekas et al.                p.M147T             N/A
  2009; Debeer et
  al. 2005; &
  Spaepen et
  al. 1991
Paznekas et                    p.G143S             N/A
  al. 2009;
  Richardson et al.
  2004; & Brueton
  et al. 1990
Orosz et al. 2018              p.G138D             N/A
Paznekas et al.                p.G138R             N/A
  2009; Paznekas et
  al. 2003; &
  Shapiro et al. 1997
Kogame et al. 2014             p.G138S             N/A
Paznekas et                    p.K134N             N/A
  al. 2009;
  Richardson et
  al. 2004; Paznekas
  et al. 2003; &
  Gladwin et al. 1997
Paznekas et al. 2009           p.K134E             N/A
  & Paznekas et
  al. 2003
Nishat et al. 2012;            p.I130T             N/A
  Paznekas et al. 2009;
  Paznekas et al. 2003;
  & Amador et al. 2008
Paznekas et al. 2009;          p.L113P             N/A
  Musa et al. 2008;
  Wiest et al. 2006; &
  Loddenkemper et
  al. 2002
Paznekas et al. 2009           p.E110D             N/A
  & Debeer et al. 2005
Paznekas et al. 2009            p.L11P             N/A
  & Kelly et al. 2006
Gabriel et al. 2011             p.L11F             N/A
  & Jamsheer et
  al. 2009
Porntaveetus et                 p.L11I             N/A
  al. 2017
Jamsheer et al. 2014           p.L106R             N/A
Paznekas et al. 2009           p.L106P             N/A
  & Nivelon-Chevallier
  et al. 1981
Paznekas et al. 2009           p.K102N             N/A
  & Paznekas et al. 2003
Paznekas et al. 2009;           p.Y98C             N/A
  Paznekas et al. 2003;
  & Wooldridge et
  al. 1977
Paznekas et al. 2009            p.V96A             N/A
Wiest et al. 2006               p.V96E             N/A
Paznekas et al. 2009            p.V96M             N/A
  & Kjaer et al. 2004
Paznekas et al. 2009            p.H95R             N/A
  & Honkaniemi et
  al. 2005
Paznekas et al. 2009;           p.L90V             N/A
  Paznekas et al. 2003;
  & Opjordsmoen and
  Nyberg-Hansen 1980
Jamsheer et al. 2014            p.S86Y             N/A
Pizzuti et al. 2004             p.R76H             N/A
Izumi et al. 2013               p.R76C             N/A
Paznekas et al. 2009;           p.R76S             N/A
  Paznekas et al. 2003;
  & Stanislaw et
  al. 1998
Choi et al. 2018               p.H74P*             N/A
Paznekas et al. 2009;           p.S69Y             N/A
  Richardson et al.
  2004; Paznekas et
  al. 2003; & Gladwin
  et al. 1997
Paznekas et al. 2009 &          p.P59H             N/A
  Vasconcellos et
  al. 2005
Paznekas et al. 2009           p.Q49dup            N/A
Pazenkas et al. 2009;          p.F52dup            N/A
  Paznekas et al. 2003;
  Weintraub et al.
  1975; & Gellis and
  Feingold 1974
Hadjichristou et                p.Q49P             N/A
  al. 2017 & Paznekas
  et al. 2009
Izumi et al. 2013               p.Q49E             N/A
Paznekas et al. 2009            p.Q49K             N/A
  & Paznekas et al. 2003
Amano et al. 2012;              p.E48K             N/A
  Feller et al. 2008;
  Paznekas et al. 2009;
  & Itro et al. 2005
Jamsheer et al. 2014            p.D47H             N/A
Tumminelli et al. 2016          p.E42Q             N/A
Gabriel et al. 2011          p.V41_A44del          N/A
Paznekas et al. 2009            p.V41L
  & Kellermayer et             p.R127H             N/A
  al. 2005                      (GJB2
                              mutation)
Park et al. 2019;               p.A40V             N/A
  Hayashi et al.
  2014; Paznekas et
  al. 2009; Debeer et
  al. 2005; & Paznekas
  et al. 2003
Wittlieb-Weber et               p.P59S             N/A
  al. 2015
Attig et al. 2016              p.I132_             N/A
                             K133delinsM
Paznekas et al. 2009            p.L7V              N/A
Himi et al. 2009                p.S5C              N/A
Pace et al. 2019                p.V96G             N/A
                                p.L26P             N/A
Totals

Sources                     Individuals      Untested
                              with a       individuals
                            molecular        with both
                            confirmed          ODDD
                              GJA1           phenotype
                            pathogenic       and known
                             variant       relative with
                                             molecular
                                           confirmation

                           Male   Female   Male   Female

Cavusoglu et al. 2019       1       0       0       0
Aminabadi et al. 2009       1       0       2       1
  & Aminabadi et
  al. 2010
Dwarakanathan et            1       1       0       0
  al. 2015 & Furuta
  et al. 2012
Quick and Dobersen 2014;    1       0       0       0
  National Center for
  Biotechnology
  Information 2020
Paznekas et al. 2003 &      1       7       4       5
  Paznekas et al. 2009
Jamsheer et al. 2010        1       0       0       0
Jamsheer et al. 2010        0       1       0       0
Paznekas et al. 2009;       0       2       0       0
  Joss et al. 2008; &
  Richardson et
  al. 2006
Paznekas et al. 2009;       0       0       4       4
  Richardson et al.
  2004; Paznekas et
  al. 2003; & Gladwin
  et al. 1997
Wang et al. 2019            1       0       0       0
Paznekas et al. 2009        1       2       0       0
  & van Steensel et
  al. 2005
Paznekas et al. 2009;       1       0       0       0
  Paznekas et al.
  2003; & Gorlin et
  al. 1963
Dwarakanathan et            0       3       1       0
  al. 2015; Paznekas
  et al. 2009; &
  Vreeburg et al. 2007
This study; Gumus           0       3       0       0
  2018; Paznekas et
  al. 2009; Paznekas
  et al. 2003; &
  Traboulsi and
  Parks 1990
Wiest et al. 2006           0       1       0       0
Paznekas et al. 2009;       1       0       4       1
  Paznekas et al.
  2003; & Norton et
  al. 1995
Park et al. 2017;           0       2       0       0
  Paznekas et al.
  2009; & Paznekas
  et al. 2003
Brice et al. 2013           1       2       1       1
Paznekas et al. 2009        0       1       0       0
Paznekas et al. 2009        1       0       0       0
  & de la Parra et
  al. 2007
Vitiello et al. 2005        3       5       3       3
  & Vingolo et
  al. 1994
Paznekas et al.             0       0       1       3
  2009; Paznekas et
  al. 2003; & Judisch
  et al. 1979
Paznekas et al. 2009        3       4       0       0
  & Paznekas et
  al. 2003
Paznekas et al. 2009        0       1       0       0
  & Debeer et
  al. 2005
Wiest et al. 2006 &         0       2       0       1
  Thomsen et
  al. 1998
Paznekas et al. 2009        0       2       0       0
  & van Es et
  al. 2007
Paznekas et al.             0       0       2       2
  2009; Richardson
  et al. 2004;
  Paznekas et al.
  2003; Gladwin et
  al. 1997; &
Schrander-Stumpel           1       0       0       0
  et al. 1993
  Tafdelen et
  al. 2018
Paznekas et al.             0       1       0       0
  2009; Debeer et
  al. 2005; &
  Spaepen et
  al. 1991
Paznekas et                 0       0       8       1
  al. 2009;
  Richardson et al.
  2004; & Brueton
  et al. 1990
Orosz et al. 2018           1       0       0       0
Paznekas et al.             1       2       2       2
  2009; Paznekas et
  al. 2003; &
  Shapiro et al. 1997
Kogame et al. 2014          1       0       0       0
Paznekas et                 0       0       0       2
  al. 2009;
  Richardson et
  al. 2004; Paznekas
  et al. 2003; &
  Gladwin et al. 1997
Paznekas et al. 2009        0       1       0       0
  & Paznekas et
  al. 2003
Nishat et al. 2012;         7       4       5       1
  Paznekas et al. 2009;
  Paznekas et al. 2003;
  & Amador et al. 2008
Paznekas et al. 2009;       2       2       1       0
  Musa et al. 2008;
  Wiest et al. 2006; &
  Loddenkemper et
  al. 2002
Paznekas et al. 2009        2       3       1       2
  & Debeer et al. 2005
Paznekas et al. 2009        0       1       0       0
  & Kelly et al. 2006
Gabriel et al. 2011         0       2       0       0
  & Jamsheer et
  al. 2009
Porntaveetus et             1       0       0       0
  al. 2017
Jamsheer et al. 2014        2       0       0       0
Paznekas et al. 2009        1       0       0       0
  & Nivelon-Chevallier
  et al. 1981
Paznekas et al. 2009        1       2       0       0
  & Paznekas et al. 2003
Paznekas et al. 2009;       1       3       1       1
  Paznekas et al. 2003;
  & Wooldridge et
  al. 1977
Paznekas et al. 2009        0       1       0       0
Wiest et al. 2006           0       1       0       0
Paznekas et al. 2009        2       2       0       0
  & Kjaer et al. 2004
Paznekas et al. 2009        0       1       0       1
  & Honkaniemi et
  al. 2005
Paznekas et al. 2009;       4       0       3       2
  Paznekas et al. 2003;
  & Opjordsmoen and
  Nyberg-Hansen 1980
Jamsheer et al. 2014        0       1       0       0
Pizzuti et al. 2004         1       0       0       0
Izumi et al. 2013           1       0       0       0
Paznekas et al. 2009;       0       2       0       2
  Paznekas et al. 2003;
  & Stanislaw et
  al. 1998
Choi et al. 2018            1       0       0       0
Paznekas et al. 2009;       0       0       2       5
  Richardson et al.
  2004; Paznekas et
  al. 2003; & Gladwin
  et al. 1997
Paznekas et al. 2009 &      4       4       1       0
  Vasconcellos et
  al. 2005
Paznekas et al. 2009        0       1       0       0
Pazenkas et al. 2009;       1       0       1       1
  Paznekas et al. 2003;
  Weintraub et al.
  1975; & Gellis and
  Feingold 1974
Hadjichristou et            1       1       0       0
  al. 2017 & Paznekas
  et al. 2009
Izumi et al. 2013           0       1       0       0
Paznekas et al. 2009        3       2       0       0
  & Paznekas et al. 2003
Amano et al. 2012;          3       0       0       0
  Feller et al. 2008;
  Paznekas et al. 2009;
  & Itro et al. 2005
Jamsheer et al. 2014        0       3       0       0
Tumminelli et al. 2016      1       0       0       0
Gabriel et al. 2011         0       1       1       2

Paznekas et al. 2009
  & Kellermayer et          0       1       0       0
  al. 2005
Park et al. 2019;           6       4       4       3
  Hayashi et al.
  2014; Paznekas et
  al. 2009; Debeer et
  al. 2005; & Paznekas
  et al. 2003
Wittlieb-Weber et           1       2       0       0
  al. 2015
Attig et al. 2016           3       2       0       0

Paznekas et al. 2009        1       0       0       0
Himi et al. 2009            0       1       0       0
Pace et al. 2019            0       1       0       0
                            0       1       0       0
Totals                      72      93      52      46

Sources                             Total individuals with
                                      the ODDD phenotype

                               Male           Female           Total

Cavusoglu et al. 2019       1     100%      0         0%         1
Aminabadi et al. 2009       3      75%      1         25%        4
  & Aminabadi et
  al. 2010
Dwarakanathan et            1      50%      1         50%        2
  al. 2015 & Furuta
  et al. 2012
Quick and Dobersen 2014;    1     100%      0         0%         1
  National Center for
  Biotechnology
  Information 2020
Paznekas et al. 2003 &      5      29%      12        71%       17
  Paznekas et al. 2009
Jamsheer et al. 2010        1     100%      0         0%         1
Jamsheer et al. 2010        0      0%       1        100%        1
Paznekas et al. 2009;       0      0%       2        100%        2
  Joss et al. 2008; &
  Richardson et
  al. 2006
Paznekas et al. 2009;       4      50%      4         50%        8
  Richardson et al.
  2004; Paznekas et
  al. 2003; & Gladwin
  et al. 1997
Wang et al. 2019            1     100%      0         0%         1
Paznekas et al. 2009        1      33%      2         67%        3
  & van Steensel et
  al. 2005
Paznekas et al. 2009;       1     100%      0         0%         1
  Paznekas et al.
  2003; & Gorlin et
  al. 1963
Dwarakanathan et            1      25%      3         75%        4
  al. 2015; Paznekas
  et al. 2009; &
  Vreeburg et al. 2007
This study; Gumus           0      0%       3        100%        3
  2018; Paznekas et
  al. 2009; Paznekas
  et al. 2003; &
  Traboulsi and
  Parks 1990
Wiest et al. 2006           0      0%       1        100%        1
Paznekas et al. 2009;       5      83%      1         17%        6
  Paznekas et al.
  2003; & Norton et
  al. 1995
Park et al. 2017;           0      0%       2        100%        2
  Paznekas et al.
  2009; & Paznekas
  et al. 2003
Brice et al. 2013           2      40%      3         60%        5
Paznekas et al. 2009        0      0%       1        100%        1
Paznekas et al. 2009        1     100%      0         0%         1
  & de la Parra et
  al. 2007
Vitiello et al. 2005        6      43%      8         57%       14
  & Vingolo et
  al. 1994
Paznekas et al.             1      25%      3         75%        4
  2009; Paznekas et
  al. 2003; & Judisch
  et al. 1979
Paznekas et al. 2009        3      43%      4         57%        7
  & Paznekas et
  al. 2003
Paznekas et al. 2009        0      0%       1        100%        1
  & Debeer et
  al. 2005
Wiest et al. 2006 &         0      0%       3        100%        3
  Thomsen et
  al. 1998
Paznekas et al. 2009        0      0%       2        100%        2
  & van Es et
  al. 2007
Paznekas et al.             2      50%      2         50%        4
  2009; Richardson
  et al. 2004;
  Paznekas et al.
  2003; Gladwin et
  al. 1997; &
Schrander-Stumpel           1     100%      0         0%         1
  et al. 1993
  Tafdelen et
  al. 2018
Paznekas et al.             0      0%       1        100%        1
  2009; Debeer et
  al. 2005; &
  Spaepen et
  al. 1991
Paznekas et                 8      89%      1         11%        9
  al. 2009;
  Richardson et al.
  2004; & Brueton
  et al. 1990
Orosz et al. 2018           1     100%      0         0%         1
Paznekas et al.             3      43%      4         57%        7
  2009; Paznekas et
  al. 2003; &
  Shapiro et al. 1997
Kogame et al. 2014          1     100%      0         0%         1
Paznekas et                 0      0%       2        100%        2
  al. 2009;
  Richardson et
  al. 2004; Paznekas
  et al. 2003; &
  Gladwin et al. 1997
Paznekas et al. 2009        0      0%       1        100%        1
  & Paznekas et
  al. 2003
Nishat et al. 2012;         12     71%      5         29%       17
  Paznekas et al. 2009;
  Paznekas et al. 2003;
  & Amador et al. 2008
Paznekas et al. 2009;       3      60%      2         40%        5
  Musa et al. 2008;
  Wiest et al. 2006; &
  Loddenkemper et
  al. 2002
Paznekas et al. 2009        3      38%      5         63%        8
  & Debeer et al. 2005
Paznekas et al. 2009        0      0%       1        100%        1
  & Kelly et al. 2006
Gabriel et al. 2011         0      0%       2        100%        2
  & Jamsheer et
  al. 2009
Porntaveetus et             1     100%      0         0%         1
  al. 2017
Jamsheer et al. 2014        2     100%      0         0%         2
Paznekas et al. 2009        1     100%      0         0%         1
  & Nivelon-Chevallier
  et al. 1981
Paznekas et al. 2009        1      33%      2         67%        3
  & Paznekas et al. 2003
Paznekas et al. 2009;       2      33%      4         67%        6
  Paznekas et al. 2003;
  & Wooldridge et
  al. 1977
Paznekas et al. 2009        0      0%       1        100%        1
Wiest et al. 2006           0      0%       1        100%        1
Paznekas et al. 2009        2      50%      2         50%        4
  & Kjaer et al. 2004
Paznekas et al. 2009        0      0%       2        100%        2
  & Honkaniemi et
  al. 2005
Paznekas et al. 2009;       7      78%      2         22%        9
  Paznekas et al. 2003;
  & Opjordsmoen and
  Nyberg-Hansen 1980
Jamsheer et al. 2014        0      0%       1        100%        1
Pizzuti et al. 2004         1     100%      0         0%         1
Izumi et al. 2013           1     100%      0         0%         1
Paznekas et al. 2009;       0      0%       4        100%        4
  Paznekas et al. 2003;
  & Stanislaw et
  al. 1998
Choi et al. 2018            1     100%      0         0%         1
Paznekas et al. 2009;       2      29%      5         71%        7
  Richardson et al.
  2004; Paznekas et
  al. 2003; & Gladwin
  et al. 1997
Paznekas et al. 2009 &      5      56%      4         44%        9
  Vasconcellos et
  al. 2005
Paznekas et al. 2009        0      0%       1        100%        1
Pazenkas et al. 2009;       2      67%      1         33%        3
  Paznekas et al. 2003;
  Weintraub et al.
  1975; & Gellis and
  Feingold 1974
Hadjichristou et            1      50%      1         50%        2
  al. 2017 & Paznekas
  et al. 2009
Izumi et al. 2013           0      0%       1        100%        1
Paznekas et al. 2009        3      60%      2         40%        5
  & Paznekas et al. 2003
Amano et al. 2012;          3     100%      0         0%         3
  Feller et al. 2008;
  Paznekas et al. 2009;
  & Itro et al. 2005
Jamsheer et al. 2014        0      0%       3        100%        3
Tumminelli et al. 2016      1     100%      0         0%         1
Gabriel et al. 2011         1      25%      3         75%        4
Paznekas et al. 2009
  & Kellermayer et          0      0%       1        100%        1
  al. 2005
Park et al. 2019;           10     59%      7         41%       17
  Hayashi et al.
  2014; Paznekas et
  al. 2009; Debeer et
  al. 2005; & Paznekas
  et al. 2003
Wittlieb-Weber et           1      33%      2         67%        3
  al. 2015
Attig et al. 2016           3      60%      2         40%        5
Paznekas et al. 2009        1     100%      0         0%         1
Himi et al. 2009            0      0%       1        100%        1
Pace et al. 2019            0      0%       1        100%        1
                            0      0%       1        100%        1
Totals                     124     47%     139        53%       263

* Unknown which specific individuals tested.

TABLE 4: Eye and ocular adnexa features reported in ODDD.

Orbit               --              Microphthalmia
                                      (110/37%)
Anterior         Anterior          Shallow anterior
  segment        chamber           chamber (12/4%)
                  Cornea        Microcornea (111/38%)

                  Sclera         Blue sclera (1/<1%)
                  Pupil          Persistent pupillary
                                  membranes (13/4%)

                   Lens           Cataracts (17/6%)
               Uvea (iris,          Pale/atrophic
              ciliary body)         irides (11/4%)

Posterior     Uvea (choroid)    Thick choroid (2/<l%)
  segment
                 Vitreous              Vitreous
                                 degeneration (1/<1%)

              Retina/fundus       Dysplastic retina/
                                    fundus (3/1%)

                Optic disc          Pale/atrophic
                                  optic disc (3/1%)

Ocular            Eyelid        Short/narrow palpebral
  adnexa                          fissures (56/19%)

                 Eyebrow/         Madarosis (19/6%)
                 eyelash

               Nasolacrimal       Nasolacrimal duct
                   duct         abnormalities (2/<l%)

Other           Refractive          Myopia (16/5%)
                  errors          (2 anisometropic)

               Eye movement       Strabismus (27/9%)
                disorders           (9 esotropic,
                                     1 exotropic)

                Additional        Glaucoma (51/17%)
              eye disorders        (4 closed-angle,
                                    1 open-angle)

             ERG/neurological    Abnormal ERG (2/<l%)

Orbit               --            Hypotelorism        Hypertelorism
                                     (24/8%)             (22/7%)

Anterior         Anterior         Deep anterior
  segment        chamber        chambers (2/< 1%)

                  Cornea          Thick corneas          Corneal
                                     (4/1%)         opacities (3/1%)
                  Sclera

                  Pupil             Eccentric
                                  pupils (3/1%)

                   Lens          Lens opacities     White retrolental
                                   (2/ < 1 %)        masses (1/<1%)

               Uvea (iris,       Uveitis (10/3%)      General iris
              ciliary body)                           abnormalities
                                                         (7/2%)
Posterior     Uvea (choroid)      Thin choroid
  segment                            (1/<1%)

                 Vitreous       Vitreous membrane      Persistent
                                  attachment to       hyperplastic
                                 optic nerve and    primary vitreous
                                  lens (1/<1%)           (1/<1%)

              Retina/fundus       Pale retina/         Thread-like
                                 fundus (2/<l%)          retinal
                                                       vasculature
                                                         (2/<l%)

                Optic disc      Dysplastic optic     Ellipsoid optic
                                  disc (2/< 1%)       disc (1/< 1%)

Ocular            Eyelid           Epicanthus          Telecanthus
  adnexa                            (36/12%)             (11/4%)

                 Eyebrow/        Flared eyebrows        Synophyrs
                 eyelash            (3/1%) (2            (1/<1%)
                                medially flared)

               Nasolacrimal     Elypolacrimation
                   duct              (1/<1%)

Other           Refractive      Elyperopia (8/3%)      Astigmatism
                  errors        (2 anisometropic)        (1/<1%)

               Eye movement     Nystagmus (8/3%)        Amblyopia
                disorders                                (3/1%)

                Additional         Paracentral
              eye disorders     scotoma (1/< 1%)

             ERG/neurological    Delayed visual         Occipital
                                evoked responses       subcortical
                                     (2/<l%)          white matter
                                                     changes (1/<1%)

Orbit               --           Short axial
                                length (4/1%)

Anterior         Anterior
  segment        chamber

                  Cornea           Corneal             Band
                                   farinata        keratopathy
                                   (1/<1%)           (1/<1%)
                  Sclera

                  Pupil

                   Lens

               Uvea (iris,        Synechiae        Hypoplastic
              ciliary body)         (4/1%)        anterior iris
                                                  stroma (3/1%)
Posterior     Uvea (choroid)
  segment
                 Vitreous
              Retina/fundus       Dystrophic       Hypoplastic
                                   retinal       macula (1/< 1%)
                                  epithelium
                                   (1/<1%)

                Optic disc       Optociliary        Optic disc
                                vein presence    hypervascularity
                                   (1/<1%)           (1/<1%)

Ocular            Eyelid        Ptosis (7/2%)    Blepharophimosis
  adnexa                                             (1/<1%)
                 Eyebrow/
                 eyelash

               Nasolacrimal
                   duct

Other           Refractive
                  errors

               Eye movement     Duane syndrome    Brown syndrome
                disorders         (2/ < 1 %)         (1/<1%)

                Additional
              eye disorders

             ERG/neurological

Orbit               --

Anterior         Anterior
  segment        chamber

                  Cornea             Corneal          Abnormal
                                    keratosis        Descemet's
                                     (1/<1%)          membrane
                                                      (1/<1%)

                  Sclera

                  Pupil

                   Lens

               Uvea (iris,         Ciliary body      Flat iris
              ciliary body)       cysts (2/< 1%)      (1/<1%)

Posterior     Uvea (choroid)
  segment
                 Vitreous

              Retina/fundus       Absent fundal
                                    glow with
                                      B-scan
                                ultrasound (1/<1%)

                Optic disc

Ocular            Eyelid        Entropion (1/<1%)    Ectropion
  adnexa                                              (1/<1%)

                 Eyebrow/
                 eyelash

               Nasolacrimal
                   duct

Other           Refractive
                  errors

               Eye movement
                disorders

                Additional
              eye disorders

             ERG/neurological

Orbit               --

Anterior         Anterior
  segment        chamber

                  Cornea          Anteriorly
                                   deviated
                                Schwalbe's line
                                    (1/< 1%)

                  Sclera

                  Pupil

                   Lens

               Uvea (iris,       Iridoschisis      Inferior iris
              ciliary body)         (1/<1%)       coloboma (1/<1%)

Posterior     Uvea (choroid)
  segment
                 Vitreous

              Retina/fundus

                Optic disc

Ocular            Eyelid         Epiblepharon         Mucosal
  adnexa                            (1/<1%)         hypertrophy
                                                      (1/<1%)

                 Eyebrow/
                 eyelash

               Nasolacrimal
                   duct

Other           Refractive
                  errors

               Eye movement
                disorders

                Additional
              eye disorders

             ERG/neurological

Orbit               --

Anterior         Anterior
  segment        chamber

                  Cornea

                  Sclera

                  Pupil

                   Lens

               Uvea (iris,       Dysplastic
              ciliary body)     iris (1/<1%)

Posterior     Uvea (choroid)
  segment
                 Vitreous

              Retina/fundus

                Optic disc

Ocular            Eyelid
  adnexa
                 Eyebrow/
                 eyelash

               Nasolacrimal
                   duct

Other           Refractive
                  errors

               Eye movement
                disorders

                Additional
              eye disorders

             ERG/neurological

TABLE 5: Common GJA1 mutations with associated eye features.

Sources               Multiple              GJA1 mutation
                     mutations?

                                  Nucleotide   Protein

Quick and Dobersen      Yes        c.605G>A    p.R202H
  2014; National                   c.717G>A    p.R239R
  Center for
  Biotechnology
  Information 2020

Paznekas et al.          No        c.605G>A    p.R202H
  2009; Paznekas
  et al. 2003

Nishat et al.            No        c.389T>C    p.I130T
  2012; Paznekas
  et al. 2009;
  Paznekas et
  al. 2003; and
  Amador et
  al. 2008

Park et al.              No        c.119C>T    p.A40V
  2019; Hayashi
  et al. 2014;
  Paznekas et
  al. 2009; Debeer
  et al. 2005; and
  Paznekas et
  al. 2003

Sources              Individuals with      Associated eye
                      GJA1 mutation           features
                      (confirmed and
                         affected
                     relatives) Total

Quick and Dobersen          1            Microphthalmia (1)
  2014; National
  Center for
  Biotechnology
  Information 2020

Paznekas et al.             17          Microphthalmia (1),
  2009; Paznekas                          microcornea (2)
  et al. 2003

Nishat et al.               17          Microphthalmia (4),
  2012; Paznekas                         hypotelorism (6),
  et al. 2009;                             cataract (1),
  Paznekas et                           pale/atrophic optic
  al. 2003; and                         disc (1), and short
  Amador et                                  palpebral
  al. 2008                                  fissures (4)

Park et al.                 17          Microphthalmia (9),
  2019; Hayashi                          hypertelorism (3),
  et al. 2014;                           hypotelorism (4),
  Paznekas et                               short axial
  al. 2009; Debeer                          length (4),
  et al. 2005; and                         cataract (1),
  Paznekas et                             microcornea (8),
  al. 2003                               thick cornea (4),
                                         macular hypoplasia
                                            (1), shallow
                                          anterior chamber
                                          (4), myopia (4),
                                           strabismus (6)
                                           (1 esotropic),
                                         glaucoma (6), and
                                           epicanthus (3)

TABLE 6: Mutant connexin-43 domains and associated phenotype.

GJA1 mutation          Protein domain        Associated phenotype
                     (amino acid range)      (no. of individuals)
                       (obtained from
                      UniProt-P17302)

p.G2fsX7                Cytoplasmic            Microcornea (7),
  (with p.R101X)     N-terminus (1-13)       microphthalmia (5),
p.G2V                                          epicanthus (4),
p.L11P                                        strabismus (3) (1
p.L11F                                        esotropic), short
p.L11I                                     palpebral fissures (2),
p.L7V                                          telecanthus (2),
p.S5C                                     amblyopia (1), dysplastic
                                           fundus (1), optociliary
                                             vein (1), dysplastic
                                            optic disc (1), pale/
                                           atrophic optic disc (1),
                                             persistent pupillary
                                          membrane (1), myopia (3),
                                                hyperopia (1)
                                          (anisometropic), glaucoma
                                               (1), ptosis (1),
                                           entropion (1), madarosis
                                           (1), hypertelorism (1),
                                               and cataract (1)

p.W25C                Transmembrane-1         Microcornea (21),
p. R33X                   (14-36)            microphthalmia (14),
p.I31M                                     short palpebral fissures
p.K23T                                         (11), persistent
p.G22E                                     pupillary membrane (6),
p.G21R                                    madarosis (6), epicanthus
p.S18P                                        (6), glaucoma (5),
p.Y17S                                       anterior iris stroma
p.L26P                                         hypoplasia (3),
                                              hypertelorism (2),
                                              cataract (2), iris
                                              abnormalities (2),
                                              blonde fundus (1),
                                            iridoschisis (1), deep
                                            anterior chamber (1),
                                          hyperopia (2), strabismus
                                              (7) (3 esotropic),
                                           amblyopia (1), nystagmus
                                               (1), ptosis (1),
                                              epiblepharon (1),
                                              nasolacrimal duct
                                             obstruction (1), and
                                             flared eyebrows (1)
                                              (medially flared)

p.Q57SfsTer6          Extracellular-1        Microphthalmia (32),
p.R76H                    (37-76)             microcornea (30),
p.R76C                                         glaucoma (15) (2
p.R76S                                         closed-angle, 1
p.H74P                                           open-angle),
p.S69Y                                       hypertelorism (11),
p.P59H                                         epicanthus (10),
p.Q49dup                                      strabismus (9) (3
p.F52dup                                      esotropic), short
p.Q49P                                     palpebral fissures (9),
p.Q49E                                           iris atrophy
p.Q49K                                       (peripupillary) (8),
p.E48K                                      cataract (6), shallow
p.D47H                                      anterior chamber (6),
p.E42Q                                        hypotelorism (5),
p.V41_A44del                                  short axial length
p.V41L (with                                   (4), myopia (4),
  p.R127H                                   corneal farinata (4),
  (GJB2 mutation))                          telecanthus (3), iris
p.A40V                                        abnormalities (2),
p.P59S                                      eccentric pupils (2),
                                             persistent pupillary
                                           membrane (2), dysplastic
                                            fundus (1), dysplastic
                                              optic (1), macular
                                          hypoplasia (1), synechiae
                                           (1), ciliary body cysts
                                              (1), deep anterior
                                            chamber (1), hyperopia
                                               (1), ptosis (1),
                                            blepharophimosis (1),
                                                madarosis (1),
                                              nasolacrimal duct
                                            abnormalities (1), and
                                             low-voltage ERG (1)

p.Y98C                Transmembrane-2         Hypertelorism (5),
p.V96A                    (77-99)              microcornea (2),
p.V96E                                       microphthalmia (3),
p.V96M                                     glaucoma (3), strabismus
p.H95R                                     (2) (1 esotropic), short
p.L90V                                     palpebral fissures (2),
p.S86Y                                          eyelid mucosal
p.V96G                                         hypertrophy (1),
                                               telecanthus (1),
                                            epicanthus (1), optic
                                              disc atrophy (1),
                                               hyperopia (1),
                                            yopia (1), strabismus
                                               (1), paracentral
                                            scotoma (1), madarosis
                                           (1), and delayed visual
                                            evoked potentials (1)

p.R101X (with          Cytoplasmic-1         Microphthalmia (20),
  p.G2fsX7)              (100-154)         microcornea (18), short
p.R101X                                    palpebral fissures (14),
p.T154N                                       hypotelorism (14),
p.T154A                                      glaucoma (9), myopia
p.R148Q                                      (7), epicanthus (5),
p.R148Ter                                  cataract (3), strabismus
p.M147T                                     (3), shallow anterior
p.G143S                                          chamber (3),
p.G138D                                       hypertelorism (2),
p.G138R                                     opaque lens (1), optic
p.G138S                                     disc hypervascularity
p.K134N                                    (1), pale/atrophic optic
p.K134E                                     disc (1), pale irides
p.I130T                                    (1), iris abnormalities
p.L113P                                     (2), astigmatism (1),
p.E110D                                      Duane syndrome (1),
p.L106R                                     ptosis (1), occipital
p.L106P                                       subcortical white
p.K102N                                      matter changes (1),
p.I132_                                       and delayed visual
  K133delinsM                                evoked responses (1)

p.F169del             Transmembrane-3          Short palpebral
                         (155-177)               fissures (1)

p.R202H (with         Extracellular-2        Microphthalmia (18),
  p.R239R)               (178-208)        uveitis (8), glaucoma (8),
p.R202H                                    microcornea (4), opaque
p.K206R                                   cornea (2), thick choroid
p.S201F                                       (2), cataract (1),
p.H194P                                    shallow anterior chamber
                                           (1), nystagmus (2), and
                                                  ptosis (1)

p.S220Y               Transmembrane-4        Microphthalmia (1),
p.V216L                  (209-231)        glaucoma (1), microcornea
                                             (1), and persistent
                                            pupillary membrane (1)

p.Y230fsX236          Transmembrane-4         Hypertelorism (2),
                       & cytoplasmic        hypotelorism (1), and
                         C-terminus          flared eyebrows (2)
                         (209-382)           (1 medially flared)

p.R239R (with           Cytoplasmic        Short palpebral fissures
  p.R202H)                                   (3), epicanthus (2),
p.I311P                  C-terminus           hypotelorism (2),
p.C260fsX306             (232-382)          microcornea (2), pale
                                           irides (2), myopia (2),
                                               hyperopia (1) (1
                                           anisometropic), corneal
                                                 opacity (1),
                                             microphthalmia (1),
                                            retinal dysplasia (1),
                                            choroid thinning (1),
                                           glaucoma (1), madarosis
                                            (1), and loss of flash
                                                   ERG (1)

Missense                  Unknown            Microphthalmia (1),
  mutation exon                                 cataract (1),
  2 (unspecified)                              microcornea (1),
                                            uveitis (1), glaucoma
                                             (1), epicanthus (1),
                                            telecanthus (1), short
                                           palpebral fissures (1),
                                                and ptosis (1)
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Title Annotation:Case Report
Author:Kumar, Virang; Couser, Natario L.; Pandya, Arti
Publication:Case Reports in Ophthalmological Medicine
Date:Apr 30, 2020
Words:10901
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