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Prenatal Diagnosis of a 2.5 Mb De Novo 17q24.1q24.2 Deletion Encompassing KPNA2 and PSMD12 Genes in a Fetus with Craniofacial Dysmorphism, Equinovarus Feet, and Syndactyly.

1. Introduction

Interstitial 17q24.1 or 17q24.2 deletions were reported in patients with malformations, facial dysmorphism, and intellectual disability [1-8]. First cases of 17q24.1 and/or 17q24.2 deletion were described by conventional cytogenetic techniques only [1-3]. Among the observed malformations, the newborn described by Levin's study had a hypertelorism associated with too large ocular globes, small and low-set ears, 2-3 toes' syndactyly, and hallux deviated by extreme flexion [1]. Conventional cytogenetic analysis revealed a 17q23.2q24.3 deletion. Clubfoot was observed in two patients [2, 3]. One case was associated with polyhydramnios at ultrasound examination during pregnancy [3]. Use of microarray comparative genomic hybridization (array-CGH) allowed the diagnosis of interstitial 17q24.1 or 17q24.2 deletions in patient suffering from intellectual disability, abnormality of the facial shape, and/or malformations [4-8]. A new syndromic entity associated with 17q24.2 microdeletion was recently described including intellectual disability, speech delay, truncal obesity, and craniofacial dysmorphism [5]. We report the first case of prenatal diagnosis of a 2.5 Mb de novo 17q24.1q24.2 deletion, by using array-CGH in a fetus with abnormal facial shape (retrognathia), talipes equinovarus, syndactyly, and mild polyhydramnios.

2. Clinical Presentation

A 27-year-old primigravida woman was referred to our prenatal diagnosis center at 25 weeks of gestation (WG) for fetal retrognathia, talipes equinovarus, and mild polyhydramnios. The couple was nonconsanguineous and the mother had history of clubfeet at birth. After confirmation of moderated fetal retrognathia, talipes equinovarus, and mild polyhydramnios, informed consent for genetic analysis was signed by the parents (according to the local ethical guidelines) and amniotic fluid was sampled at 25 WG.

After genetic counseling and according to the French Law, the pregnancy was terminated at 30 WG. The couple agreed to an external examination of the fetus only. The weight of the male fetus was evaluated at the 60th percentile (1295 g) as well as the length (crown-heel: 41 cm) and head circumference (28 cm). External examination revealed a craniofacial dysmorphism including dolichocephaly, hypertelorism, epicanthus, proptosis, convex nasal ridge, retrognathia, micrognathia, and small and low-set ears with prominent antitragus, underfolded helix, and absence of right earlobe. In addition, bilateral 2-3 toes' cutaneous syndactyly, extreme flexion contracture of the hallux, and talipes equinovarus were associated (Figure 1(a)). Skeletal X-ray and placental examination were normal according to gestational age.

3. Cytogenetics

Chromosomes were obtained using conventional cytogenetic techniques from amniotic fluid cells. Standard karyotype analysis performed on cultured amniotic fluid cells showed a normal male 46,XY karyotype. Agilent oligonucleotide Human PreCytoNem 105K array-CGH (Agilent Technologies, Santa Clara, California, USA) was used to detect chromosomal abnormalities in the fetus. Array-CGH realized on DNA obtained from uncultured amniotic fluid cells revealed an interstitial deletion of the long arm of chromosome 17 (Figure 1(b)). The proximal breakpoint was located on 17q24.1 (position min 63,739,282, position max 63,685,334) and the distal breakpoint was located on 17q24.2 (position min 66,303,332, position max 66,364,849) (genome build hg19). Thus a minimal 2.5 Mb region was deleted. A total of 20 genes are referenced within the deleted region (Supplementary Table I in Supplementary Material available online at https://doi.org/10.1155/2017/7803136). ArrayCGH results were confirmed by FISH (Fluorescence In Situ Hybridization) using BAC (Bacterial Artificial Chromosome) probes. FISH analyses were performed on metaphase spreads and interphasic nuclei of both cultured amniotic fluid cells and parental lymphocytes. BAC clones specific for the 17q chromosomal regions were used (RP11-74H8 and RP11-162L11 located at 17q24.2, RP11-342F21 located at 17q12) (Bluegnome, Amplitech, Compiegne, France). Both RP11-74H8 and RP11162L11 BAC probes gave one signal on normal chromosome 17 and no signal on deleted chromosome 17 (data not shown). FISH analyses on parents' cells were normal and thus indicated a de novo origin for the deletion. In summary, the fetus had a 2.5 Mb de novo 17q24.1q24.2 deletion. Based on the ISCN 2016 nomenclature, the formula was as follows:

46,XY.ish del(17)(q24.2q24.2)(RP11-74H8-,RP11 162L11-)dn .arr[hg19] 17q24.1q24.2(63739282_66303332)x1 dn

4. Discussion

Deletion of the 17q24.1q24.2 region is an entity described postnatally in patients suffering from intellectual disability, abnormality of the facial shape, and/or malformations. To our knowledge this is the first report in a fetus. Among the previously described patients, 20 patients were analyzed using array-CGH. Among them, 13 cases of interstitial deletion of 17q region overlapping with the deletion of the fetus were phenotypically described (Table 1). Eleven cases were published and 2 were described in DECIPHER database [9] (Figure 1(c)). Most of these patients presented mental or psychomotor delays in association with abnormality of the fingers or toes (2-3 toes' syndactyly), obesity, failure to thrive, and facial dysmorphism with hypertelorism, prominent nose, ears abnormality (malformation or low-set ears), thin lips, and teeth abnormality (Table 1). We observed some common features with the patient described by Blyth et al.'s study presenting hypertelorism, bilateral 2-3 toes' syndactyly, beaking of the nose, and epicanthus [4]. The deletion 17q24.2q24.3 was larger than ours and other features were absent or nonevaluable in prenatal examination (postnatal growth retardation, freckles, and lentigines). Vergult et al. described a new 17q24.2 microdeletion syndrome characterized by the association of intellectual disability, pronounced speech delay, truncal obesity, and facial dysmorphism [5]. After this first description, two other cases were published with the same smallest region of overlap and phenotype close to cases of Vergult et al.'s study [6,7]. More recently, Kury et al. published a cohort of patients with mutations or CNV deletions encompassing PSMD12, located in 17q24.2 [8]. These patients presented intellectual disability associated with craniofacial dysmorphism. We identified 20 known coding genes within the deleted region of our case (Supplementary Table I). Among them, 14 genes are OMIM morbid genes. Some of them were associated with human pathogenicity. Among them we discuss KPNA2 and PSMD12 genes, also deleted in the patients of Stewart, Bartnik, Vergult (patients 3 and 4), and Kury (patients 5 and 6) studies [5-8]. KPNA2 encodes for karyopherin alpha-2 and is involved in the nuclear import of proteins. KPNA2 is involved in the Nijmegen breakage syndrome (NBS). KPNA2 interacts with the NBS gene product NBS1 involved in checkpoint arrest and repair-response to DNA double-strand breaks [10]. Mutations in NBS1 were identified in most patients with NBS [10]. The NBS is a rare autosomal recessive syndrome characterized by microcephaly at birth, intrauterine growth retardation, short stature, chromosomal instability, immunodeficiency, and predisposition to malignancy [11]. Craniofacial features can associate palpable anterior fontanel, prominent midface, sloping forehead, retrognathia, upslanted palpebral fissures, long, beaked, or upturned with anteverted nostrils nose, and in half of the patients clinodactyly of the 5th fingers and partial 2-3 toes' syndactyly [11]. Our case presented some common characteristics with patients encompassing NBS: retrognathia, convex nasal ridge, and cutaneous 2-3 toes' syndactyly. The proposed mechanism in this case is KPNA2 haploinsufficiency responsible for decreased expression of KPNA2. KPNA2 has a high haploinsufficiency score in DECIPHER database (HI index = 10.31%), and it is more likely to exhibit haploinsufficiency [12]. Moreover, according to the ExAC browser, with a probability of loss-of-function intolerance of 0.73, KPNA2 is predicted to be moderately intolerant to loss-of-function mutations [13]. PSMD12 encodes the subunit PSMD12 of the 26S proteasome, involved in degradation of polyubiquitinated proteins. Utilizing zebrafish, Kiiry et al. revealed that PSMD12 was important in brain, renal, and craniofacial development [8]. Thereby, PSMD12 haploinsufficiency could explain craniofacial dysmorphism observed in our case. The mother of the fetus had in her clinical history clubfeet at birth, without chromosomal rearrangement. With this information, it is difficult to establish a genotypephenotype correlation between the 17q24.1q24.2 deletion and the deformities of the feet observed in the fetus.

In conclusion we reported the first case of prenatal diagnosis of 17q24.1q24.2 deletion in a fetus with polyhydramnios, abnormal facial shape, 2-3 toes' syndactyly, and talipes equinovarus. The deletion encompassed KPNA2 and PSMD12 which could be involved in the fetal phenotype associated with 17q24.1q24.2 deletion. This report highlights the necessity to perform array-CGH also in prenatal diagnosis in case of minor echographic signs association.

Additional Points

Web Resources. This study makes use of data generated by the DECIPHER community. A full list of centres who contributed to the generation of the data is available from https://decipher.sanger.ac.uk and via email from decipher@sanger.ac.uk.

https://doi.org/10.1155/2017/7803136

Conflicts of Interest

The authors declare that there are no conflicts of interest regarding the publication of this paper.

Acknowledgments

The authors thank Dr. Marie-Line Jacquemont and Dr. Miranda Splitt for the clinical data of their patients. They also thank the DGOS (Direction Generale de l'Organisation des Soins) for their support in the development of array-CGH platform (Paris Sud).

References

[1] M. L. Levin, L. G. Shaffer, R. A. Lewis, M. V Gresik, and J. R. Lupski, "Unique de novo interstitial deletion of chromosome 17, del(17) (q23.2q24.3) in a female newborn with multiple congenital anomalies," American Journal of Medical Genetics, vol. 55, no. 1, pp. 30-32,1995.

[2] J. A. Thomas, D. K. Manchester, K. E. Prescott, R. Milner, L. McGavran, and M. M. Cohen Jr., "Hunter-McAlpine craniosynostosis phenotype associated with skeletal anomalies and interstitial deletion of chromosome 17q," American Journal of Medical Genetics, vol. 62, no. 4, pp. 372-375, 1996.

[3] P. N. Olney, L. S. Kean, D. Graham, L. J. Elsas, and K. M. May, "Campomelic syndrome and deletion of SOX9," American Journal of Medical Genetics, vol. 84, no. 1, pp. 20-24,1999.

[4] M. Blyth, S. Huang, V. Maloney, J. A. Crolla, and I. Karen Temple, "A 2.3 Mb deletion of 17q24.2-q24.3 associated with 'Carney Complex plus," European Journal of Medical Genetics, vol. 51, no. 6, pp. 672-678, 2008.

[5] S. Vergult, A. Dauber, B. Delle Chiaie et al., "17q24.2 Microdeletions: a new syndromal entity with intellectual disability, truncal obesity, mood swings and hallucinations," European Journal of Human Genetics, vol. 20, no. 5, pp. 534-539, 2012.

[6] M. Bartnik, B. Nowakowska, K. Derwinska et al., "Application of array comparative genomic hybridization in 256 patients with developmental delay or intellectual disability," Journal of Applied Genetics, vol. 55, no. 1, pp. 125-144, 2014.

[7] D. R. Stewart, A. Pemov, J. J. Johnston et al., "Dubowitz syndrome is a complex comprised of multiple, genetically distinct and phenotypically overlapping disorders," PLoS ONE, vol. 9, no. 6, Article ID e98686, 2014.

[8] S. Kury, T. Besnard, F. Ebstein et al., "De novo disruption of the proteasome regulatory subunit PSMD12 causes a syndromic neurodevelopmental disorder," The American Journal of Human Genetics, vol. 100, no. 2, pp. 352-363, 2017

[9] H. V. Firth, S. M. Richards, A. P. Bevan et al., "DECIPHER: database of chromosomal imbalance and phenotype in humans using ensembl resources," The American Journal of Human Genetics, vol. 84, no. 4, pp. 524-533, 2009.

[10] S.-F. Tseng, C.-Y. Chang, K.-J. Wu, and S.-C. Teng, "Importin KPNA2 is required for proper nuclear localization and multiple functions of NBS1," The Journal of Biological Chemistry, vol. 280, no. 47, pp. 39594-39600, 2005.

[11] K. H. Chrzanowska, H. Gregorek, B. Dembowska-Bagmska, M. A. Kalina, and M. Digweed, "Nijmegen breakage syndrome (NBS)," Orphanet Journal of Rare Diseases, vol. 7, article 13,2012.

[12] N. Huang, I. Lee, E. M. Marcotte, and M. E. Hurles, "Characterising and predicting haploinsufficiency in the human genome," PLoS Genetics, vol. 6, no. 10, Article ID e1001154, 2010.

[13] M. Lek, K. J. Karczewski, E. V. Minikel et al., "Analysis of protein-coding genetic variation in 60,706 humans," Nature, vol. 536, no. 7616, pp. 285-291, 2016.

Marie-Emmanuelle Naud, (1,2) Lucie Tosca, (1,2) Jelena Martinovic, (3) Julien Saada, (4) Corinne Metay, (1) Lo'ic Drevillon, (1) Virginie Benoit, (1) Sophie Brisset, (1,2) and Gerard Tachdjian (1,2)

(1) AP-HP, Service d'Histologie, Embryologie et Cytogenetique, HOpitaux Universitaires Paris Sud, Site Antoine Beclere, Clamart, France

(2) Paculte de Medecine Paris Sud, Universite Paris Sud, Le Kremlin BicOtre, France

(3) AP-HP, Unite de Fcetopathologie, HOpitaux Universitaires Paris Sud, Site Antoine Beclere, Clamart, France

(4) AP-HP, Service de Gynecologie Obstetrique, HOpitaux Universitaires Paris Sud, Site Antoine Beclere, Clamart, France

Correspondence should be addressed to Lucie Tosca; lucie.tosca@aphp.fr

Received 22 December 2016; Revised 4 March 2017; Accepted 14 March 2017; Published 29 March 2017

Academic Editor: Evica Rajcan-Separovic

Caption: Figure 1: Fetal phenotype at 30 WG, fetal cytogenetic assays, and profile of the overlapping deletions described by array-CGH. (a) Fetal phenotype: face; right profile global view of the feet showing equinovarus feet and extreme flexion of the hallux; right foot with 2-3 toes' cutaneous syndactyly. (b) Agilent PreCytoNem 105K array-CGH profile of chromosome 17 showing a 2.5 Mb 17q24.1q24.2 deletion. (c) Profile of the overlapping deletions described by array-CGH (patients of Blyth et al. and Stewart et al. were remapped in hg19).
Table 1: Phenotypes of the patients described by array-CGH with a
deletion overlapping with our case.

                            Decipher    Decipher    Blyth et al.
                             300694      273548       2008 [4]

17q deletion (cytoband)       q24.2       q24.2      q24.2q24.3
Size (Mb)                     1,19        0,23          2,26
Age at phenotypic           Childhood   Postnatal     12 years
description
Parental origin                DN          MH            DN
Craniofacial dysmorphism        +           +            +
Triangular face                 -           -            -
Round face                      -           -            -
Small/narrow palpebral          -           -            -
fissures
Downlanting palpebral           +           -            -
fissures
Ptosis                          -           -            -
Hypertelorism                   +           -            +
Bulbous/prominent nose          -           -            +
Broad nasal bridge              -           -            +
Short philtrum                  -           -            -
Thin lips                       +           -            +
Arched or cleft palate          -           -            +
Abnormality of the teeth        -           -            +
Retrognathia/micrognathia       -           -            +
Ears abnormality                -           -            -
Dolichocephaly                  -           -            -
Microcephaly                    -           +            +
Hearing impairment              -           -            -
Visual impairment               -           -            +
Malformation of the             -           -            NR
heart/great vessels
Mental/psychomotor              +           +            +
retardation
Behavioural/psychiatric         -           -            -
abnormality
Seizures                        -           -            -
Polyhydramnios                  -           -            NR
Intrauterine growth             -           -            +
retardation
Feeding difficulties            -           -            +
Failure to thrive/short         +           -            +
stature
Obesity                         -           -            -
Skeletal features               -           -            NR
Joint anomalies                 -           -            NR
Abnormality of skin             -           -            +
Equinovarus feet                -           -            NR
Abnormality of the              -           -            +
fingers/toes
Clinodactyly of fifth           -           -            +
finger/toes
2-3 toes' syndactyly            -           -            +

                            Vergult et al.   Vergult et al.
                               2012 [5]         2012 [5]
                              Patient 1        Patient 2

17q deletion (cytoband)       q23.3q24.2       q24.1q24.2
Size (Mb)                        3,11             1,71
Age at phenotypic              28 years         11 years
description
Parental origin                   DN               DN
Craniofacial dysmorphism          +                +
Triangular face                   -                +
Round face                        -                +
Small/narrow palpebral            -                -
fissures
Downlanting palpebral             +                -
fissures
Ptosis                            -                +
Hypertelorism                     +                +
Bulbous/prominent nose            -                +
Broad nasal bridge                -                -
Short philtrum                    -                -
Thin lips                         +                +
Arched or cleft palate            -                +
Abnormality of the teeth          +                -
Retrognathia/micrognathia         -                +
Ears abnormality                  +                +
Dolichocephaly                    NR               NR
Microcephaly                      -                -
Hearing impairment                -                +
Visual impairment                 +                -
Malformation of the               +                -
heart/great vessels
Mental/psychomotor                +                +
retardation
Behavioural/psychiatric           +                -
abnormality
Seizures                          +                -
Polyhydramnios                    -                NR
Intrauterine growth               -                -
retardation
Feeding difficulties              +                +
Failure to thrive/short           -                +
stature
Obesity                           +                +
Skeletal features                 +                +
Joint anomalies                   +                -
Abnormality of skin               -                -
Equinovarus feet                  -                -
Abnormality of the                +                +
fingers/toes
Clinodactyly of fifth             -                +
finger/toes
2-3 toes' syndactyly              -                -

                            Vergult et al.   Vergult et al.
                               2012 [5]         2012 [5]
                              Patient 3        Patient 4

17q deletion (cytoband)         q24.2          q24.2q24.3
Size (Mb)                        2,11             4,16
Age at phenotypic              28 years        2.5 years
description
Parental origin                   DN               DN
Craniofacial dysmorphism          +                +
Triangular face                   -                +
Round face                        +                +
Small/narrow palpebral            +                +
fissures
Downlanting palpebral             -                -
fissures
Ptosis                            +                +
Hypertelorism                     +                +
Bulbous/prominent nose            +                +
Broad nasal bridge                +                +
Short philtrum                    +                -
Thin lips                         +                +
Arched or cleft palate            -                -
Abnormality of the teeth          +                +
Retrognathia/micrognathia         -                +
Ears abnormality                  +                +
Dolichocephaly                    NR               NR
Microcephaly                      -                +
Hearing impairment                +                +
Visual impairment                 -                -
Malformation of the               NR               +
heart/great vessels
Mental/psychomotor                +                +
retardation
Behavioural/psychiatric           +                -
abnormality
Seizures                          +                -
Polyhydramnios                    NR               NR
Intrauterine growth               +                +
retardation
Feeding difficulties              +                +
Failure to thrive/short           +                +
stature
Obesity                           +                +
Skeletal features                 +                NR
Joint anomalies                   +                +
Abnormality of skin               +                +
Equinovarus feet                  -                NR
Abnormality of the                +                +
fingers/toes
Clinodactyly of fifth             +                -
finger/toes
2-3 toes' syndactyly              +                +

                            Bartnik et al.   Stewart et al.
                               2014 [6]         2014 [7]

17q deletion (cytoband)         q24.2          q24.2q24.3
Size (Mb)                        1,9              3,89
Age at phenotypic               1 year          16 years
description
Parental origin                   DN               DN
Craniofacial dysmorphism          +                +
Triangular face                   NR               -
Round face                        NR               -
Small/narrow palpebral            NR               +
fissures
Downlanting palpebral             NR               -
fissures
Ptosis                            NR               -
Hypertelorism                     NR               +
Bulbous/prominent nose            NR               +
Broad nasal bridge                NR               +
Short philtrum                    NR               +
Thin lips                         NR               NR
Arched or cleft palate            NR               -
Abnormality of the teeth          NR               +
Retrognathia/micrognathia         NR               -
Ears abnormality                  NR               +
Dolichocephaly                    NR               -
Microcephaly                      NR               -
Hearing impairment                NR               -
Visual impairment                 NR               +
Malformation of the               NR               +
heart/great vessels
Mental/psychomotor                +                +
retardation
Behavioural/psychiatric           NR               +
abnormality
Seizures                          NR               -
Polyhydramnios                    NR               -
Intrauterine growth               NR               +
retardation
Feeding difficulties              NR               +
Failure to thrive/short           NR               +
stature
Obesity                           +                -
Skeletal features                 NR               +
Joint anomalies                   NR               -
Abnormality of skin               NR               +
Equinovarus feet                  NR               -
Abnormality of the                NR               +
fingers/toes
Clinodactyly of fifth             NR               -
finger/toes
2-3 toes' syndactyly              NR               +

                            Kiiry et al.   Kiiry et al.
                              2017 [8]       2017 [8]
                             Patient 5      Patient 6

17q deletion (cytoband)      q23.3q24.2       q24.2
Size (Mb)                       1,37           4,06
Age at phenotypic            1.5 years      3.5 years
description
Parental origin                  DN             DN
Craniofacial dysmorphism         +              +
Triangular face                  -              -
Round face                       -              -
Small/narrow palpebral           -              -
fissures
Downlanting palpebral            -              -
fissures
Ptosis                           -              -
Hypertelorism                    +              +
Bulbous/prominent nose           -              -
Broad nasal bridge               -              -
Short philtrum                   -              -
Thin lips                        -              -
Arched or cleft palate           -              -
Abnormality of the teeth         -              -
Retrognathia/micrognathia        +              -
Ears abnormality                 -              +
Dolichocephaly                   -              -
Microcephaly                     +              -
Hearing impairment               -              +
Visual impairment                -              -
Malformation of the              +              +
heart/great vessels
Mental/psychomotor               +              +
retardation
Behavioural/psychiatric          -              NR
abnormality
Seizures                         -              -
Polyhydramnios                   NR             NR
Intrauterine growth              NR             +
retardation
Feeding difficulties             -              +
Failure to thrive/short          +              +
stature
Obesity                          -              -
Skeletal features                -              -
Joint anomalies                  -              -
Abnormality of skin              -              -
Equinovarus feet                 -              -
Abnormality of the               -              +
fingers/toes
Clinodactyly of fifth            -              -
finger/toes
2-3 toes' syndactyly             -              +

                            Kiiry et al.   Kiiry et al.    Present
                              2017 [8]       2017 [8]        Case
                             Patient 9      Patient 10

17q deletion (cytoband)        q24.2          q24.2       q24.1q24.2
Size (Mb)                       0,84           0,62          2,5
Age at phenotypic            4.5 years       9 years       Prenatal
description
Parental origin                  DN             DN            DN
Craniofacial dysmorphism         +              +             +
Triangular face                  -              -             -
Round face                       -              -             -
Small/narrow palpebral           -              -             -
fissures
Downlanting palpebral            -              -             -
fissures
Ptosis                           -              -             NA
Hypertelorism                    -              -             +
Bulbous/prominent nose           +              +             -
Broad nasal bridge               -              -             -
Short philtrum                   +              -             -
Thin lips                        -              -             -
Arched or cleft palate           +              -             -
Abnormality of the teeth         -              -             NA
Retrognathia/micrognathia        +              -             +
Ears abnormality                 +              +             +
Dolichocephaly                   -              -             +
Microcephaly                     -              -             -
Hearing impairment               -              -             NA
Visual impairment                -              -             NA
Malformation of the              -              -             NA
heart/great vessels
Mental/psychomotor               +              +             NA
retardation
Behavioural/psychiatric          NR             +             NA
abnormality
Seizures                         -              +             NA
Polyhydramnios                   NR             -             +
Intrauterine growth              +              +             -
retardation
Feeding difficulties             +              -             NA
Failure to thrive/short          +              -             NA
stature
Obesity                          -              -             NA
Skeletal features                +              -             -
Joint anomalies                  -              -             +
Abnormality of skin              -              -             -
Equinovarus feet                 -              -             +
Abnormality of the               +              -             +
fingers/toes
Clinodactyly of fifth            -              -             -
finger/toes
2-3 toes' syndactyly             +              -             +

+: clinical feature present; clinical feature absent; NA: not
applicable; NR: not reported; DN: de novo; MH: mother inherited.
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Title Annotation:Case Report
Author:Naud, Marie-Emmanuelle; Tosca, Lucie; Martinovic, Jelena; Saada, Julien; Metay, Corinne; Drevillon,
Publication:Case Reports in Genetics
Article Type:Clinical report
Date:Jan 1, 2017
Words:3051
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