A novel mutation in MERTK for rod-cone dystrophy in a North Indian family

To identify the underlying genetic defect of childhood-onset severe rod-cone dystrophy (RCD) in a consanguineous family from North India with autosomal recessive retinitis pigmentosa. A detailed family history, clinical data, and blood samples were collected from 11 members of the family, including 4 affected by an autosomal recessive rod-cone dystrophy (arRCD), and DNA was extracted. Whole-exome sequencing (WES) was performed on DNA samples of proband and her unaffected maternal uncle. Ion Reporter software (ver. 4.4) was used for the annotation of variants obtained by WES. The variants detected in proband were tested for validation in all other affected and unaffected family members using Sanger sequencing technique. We have identified a novel nonsense mutation—c.1647T>G (p.Tyr549Ter)—in the exon 11 of MERTK that co-segregated completely with the disease phenotype in all the 4 affected members and was not observed in the 7 unaffected members of the family. This mutation was also not detected in 120 ethnically matched controls (240 chromosomes), hence excluding it as a polymorphism. MERTK has a role in retinal pigment epithelium as a regulator of rod outer segments’ phagocytosis. Due to c.1647T > G substitution, the stop codon (p.Tyr549Ter) appears early in the transcript. It seems that either the altered transcript would degenerate through nonsense-mediated decay (NMD) or potentially form truncated protein lacking a functionally important domain (i.e., tyrosine kinase domain). These findings thus further expand the mutation spectrum in MERTK and substantiate its role in the pathogenesis of retinal dystrophy. Identifier la mutation génétique sous-jacente dans la dystrophie rétinienne mixte à bâtonnets prédominants (RCD, rod-cone dystrophy) grave de l’enfance au sein d’une famille consanguine du nord de l’Inde présentant une forme autosomique récessive de rétinite pigmentaire. On a noté les antécédents familiaux détaillés, pris en compte les données cliniques et recueilli des échantillons de sang auprès de 11 membres de la famille, y compris des 4 sujets qui présentaient une RCD autosomique récessive; on a également prélevé des échantillons d’ADN. Le séquençage de l’exome entier (WES, pour whole-exome sequencing) a été réalisé sur les échantillons d’ADN de la proposante et de son oncle maternel sans dystrophie. Le logiciel Ion Reporter (version 4.4) a servi à annoter les variants obtenus par le WES. Les variants décelés chez la proposante ont fait l’objet