Novel molecular, structural and clinical findings in an Italian cohort of congenital cataract

先证者 遗传学 表型 外显子组测序 生物 队列 基因 外显子组 候选基因 医学 生物信息学 突变 内科学
作者
Mauro Lecca,Lucia Mauri,Simone Gana,Alessandra Longo,Federica Morelli,Roberta Nicotra,Massimo Plumari,Jessica Galli,Fabio Sirchia,Enza Maria Valente,Ugo Cavallari,Marco Mazza,Sabrina Signorini,Edoardo Errichiello
出处
期刊:Clinical Genetics [Wiley]
卷期号:106 (4): 403-412
标识
DOI:10.1111/cge.14568
摘要

Abstract The 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.
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