Juvenile-Onset Diabetes and Congenital Cataract: “Double-Gene” Mutations Mimicking a Syndromic Diabetes Presentation

Genes

Céline Derbois¹  Patrick Baz²  Marc Nicolino³  Valérie Senée⁴  Claire Vandiedonck⁴  Anne Philippi⁴  Caroline Lenfant⁴  Cécile Julier⁴  Anne Degavre⁴  Pierre Zalloua⁵ 

[1] Centre National de Recherche en Génomique Humaine, Institut de Biologie François Jacob, Commissariat à l’Energie Atomique, Evry 91057, France;Department of Ophthalmology, Hôtel Dieu Hospital, Beirut 166830, Lebanon;Hôpital Femme-Mère-Enfant, Division of Pediatric Endocrinology, Hospices Civils de Lyon, Université Lyon 1, Bron cedex 69677, France;INSERM UMR-S 958, Faculté de Médecine Paris Diderot, University Paris 7 Denis-Diderot, Sorbonne Paris Cité, Paris 75010, France;School of Medicine, Lebanese American University, Beirut 1102 2801, Lebanon;

关键词: monogenic diabetes;    congenital cataract;    syndrome;    whole exome sequencing;    penetrance;    consanguinity;   

DOI  :  10.3390/genes8110309

来源: DOAJ

【 摘 要 】

Monogenic forms of diabetes may account for 1–5% of all cases of diabetes, and may occur in the context of syndromic presentations. We investigated the case of a girl affected by insulin-dependent diabetes, diagnosed at 6 years old, associated with congenital cataract. Her consanguineous parents and her four other siblings did not have diabetes or cataract, suggesting a recessive syndrome. Using whole exome sequencing of the affected proband, we identified a heterozygous p.R825Q ABCC8 mutation, located at the exact same amino-acid position as the p.R825W recurring diabetes mutation, hence likely responsible for the diabetes condition, and a homozygous p.G71S mutation in CRYBB1, a gene known to be responsible for congenital cataract. Both mutations were predicted to be damaging and were absent or extremely rare in public databases. Unexpectedly, we found that the mother was also homozygous for the CRYBB1 mutation, and both the mother and one unaffected sibling were heterozygous for the ABCC8 mutation, suggesting incomplete penetrance of both mutations. Incomplete penetrance of ABCC8 mutations is well documented, but this is the first report of an incomplete penetrance of a CRYBB1 mutation, manifesting between susceptible subjects (unaffected mother vs. affected child) and to some extent within the patient herself, who had distinct cataract severities in both eyes. Our finding illustrates the importance of family studies to unmask the role of confounding factors such as double-gene mutations and incomplete penetrance that may mimic monogenic syndromes including in the case of strongly evocative family structure with consanguinity.

【 授权许可】

Unknown