Affiliation:
1. Department of Molecular Medicine University of Pavia Pavia Italy
2. Medical Genetics Unit Department of Laboratory Medicine, ASST Grande Ospedale Metropolitano Niguarda Milan Italy
3. Medical Genetics Unit IRCCS Mondino Foundation Pavia Italy
4. Pediatric Ophthalmology Unit ASST Grande Ospedale Metropolitano Niguarda Milan Italy
5. European Reference Network on Eye Diseases (ERN‐EYE) ASST Grande Ospedale Metropolitano Niguarda Milan Italy
6. Developmental Neuro‐ophthalmology Unit IRCCS Mondino Foundation Pavia Italy
7. Department of Brain and Behavioural Sciences University of Pavia Pavia Italy
8. Department of Clinical and Experimental Sciences University of Brescia Brescia Italy
9. Unit of Child Neurology and Psychiatry ASST Spedali Civili of Brescia Brescia Italy
10. Medical Genetics Unit IRCCS San Matteo Foundation Pavia Italy
Abstract
AbstractThe current genetic diagnostic workup of congenital cataract (CC) is mainly based on NGS panels, whereas exome sequencing (ES) has occasionally been employed. In this multicentre study, we investigated by ES the detection yield, mutational spectrum and genotype–phenotype correlations in a CC cohort recruited between 2020 and mid‐2022. The cohort consisted of 67 affected individuals from 51 unrelated families and included both non‐syndromic (75%) and syndromic (25%) phenotypes, with extra‐CC ocular/visual features present in both groups (48% and 76%, respectively). The functional effect of variants was predicted by 3D modelling and hydropathy properties changes. Variant clustering was used for the in‐depth assessment of genotype–phenotype correlations. A diagnostic (pathogenic or likely pathogenic) variant was identified in 19 out of 51 probands/families (~37%). In a further 14 probands/families a candidate variant was identified: in 12 families a VUS was detected, of which 9 were considered plausibly pathogenic (i.e., 4 or 5 points according to ACMG criteria), while in 2 probands ES identified a single variant in an autosomal recessive gene associated with CC. Eighteen probands/families, manifesting primarily non‐syndromic CC (15/18, 83%), remained unsolved. The identified variants (8 P, 12 LP, 10 VUS‐PP, and 5 VUS), half of which were unreported in the literature, affected five functional categories of genes involved in transcription/splicing, lens formation/homeostasis (i.e., crystallin genes), membrane signalling, cell–cell interaction, and immune response. A phenotype‐specific variant clustering was observed in four genes (KIF1A, MAF, PAX6, SPTAN1), whereas variable expressivity and potential phenotypic expansion in two (BCOR, NHS) and five genes (CWC27, KIF1A, IFIH1, PAX6, SPTAN1), respectively. Finally, ES allowed to detect variants in six genes not commonly included in commercial CC panels. These findings broaden the genotype–phenotype correlations in one of the largest CC cohorts tested by ES, providing novel insights into the underlying pathogenetic mechanisms and emphasising the power of ES as first‐tier test.