Novel phenotypes and loci identified through clinical genomics approaches to pediatric cataract

Abstract

Pediatric cataract is highly heterogeneous clinically and etiologically. While mostly isolated, cataract can be part of many multisystem disorders, further complicating the diagnostic process. In this study, we applied genomic tools in the form of a multi-gene panel as well as whole-exome sequencing on unselected cohort of pediatric cataract (166 patients from 74 families). Mutations in previously reported cataract genes were identified in 58% for a total of 43 mutations, including 15 that are novel. GEMIN4 was independently mutated in families with a syndrome of cataract, global developmental delay with or without renal involvement. We also highlight a recognizable syndrome that resembles galactosemia (a fulminant infantile liver disease with cataract) caused by biallelic mutations in CYP51A1. A founder mutation in RIC1 (KIAA1432) was identified in patients with cataract, brain atrophy, microcephaly with or without cleft lip and palate. For nonsyndromic pediatric cataract, we map a novel locus in a multiplex consanguineous family on 4p15.32 where exome sequencing revealed a homozygous truncating mutation in TAPT1. We report two further candidates that are biallelically inactivated each in a single cataract family: TAF1A (cataract with global developmental delay) and WDR87 (non-syndromic cataract). In addition to positional mapping data, we use iSyTE developmental lens expression and gene-network analysis to corroborate the proposed link between the novel candidate genes and cataract. Our study expands the phenotypic, allelic and locus heterogeneity of pediatric cataract. The high diagnostic yield of clinical genomics supports the adoption of this approach in this patient group.

Clinical and genetic characteristics of Chinese patients with familial or sporadic pediatric cataract

“…CRYGC c.233C > T; p.(Ser78Phe) caused nuclear cataracts, and CRYAA c.61C > T; p.(Arg21Trp) produced perinuclear cataracts and microphthalmia. A hotspot mutation c.70C > A; p.(Pro24Thr) and a previously reported mutation c.134 T > C; p.(Leu45Pro) in CRYGD were identified in family #5 and sporadic case #2, with no phenotypic information available [10–12].

Fig.

…”

“…(Pro24Thr)1st Greek keyT, D, B-PRef [10, 11]S#2MBirthUnknown typeSporadic->new AD CRYGD NM_006891.3 c.134T>Cp. (Leu45Pro)2nd Greek keyD, D, D-PRef [12]F#6FBirthTotal cataract, strabismus, nystagmus-AD CRYGD NM_006891.3 c.309dupp. (Glu104Argfs*4)---PRef [36]S#3FBirthTotal cataract, nystagmus-Sporadic->new AD CRYGD NM_006891.3 c.418C>Tp.…”

“…Thus, growth hormone levels, neurotrophic keratitis, orbital myopathy, and skeletal dysplasia should be monitored through later follow-ups. Other genes, such as AGK and LONP1, are known to be mutated in syndromic forms of cataract and have also been reported to cause apparently non-syndromic cataract [12, 31]. IARS2 might be the third example of such genes that can be mutated in both syndromic and non-syndromic forms of pediatric cataract.…”

“…In recent years, multiple cataract-targeted gene panels have been developed with detection rates of 26–75% [8, 12, 25, 26, 32–34]. We investigated 16 familial and 23 sporadic cases with pediatric cataract in the Chinese population and achieved an overall mutation detection rate of 58.97%, which is almost identical to those reported in similar studies of patients from South Eastern Australia (62%) [25], China (62.96%) [32], and Saudi Arabia(58%) [12], including zero, 7.4 and 23% of sporadic cases, respectively.…”

Role of Protein-Protein Interactions in Metabolism: Genetics, Structure, Function

“…A mutation of Arg277 to Cys resulted in neurologically and systemically normal children with pediatric cataract (Aldahmesh et al, 2012;Khan et al, 2015). However, three other rare variants were clearly pathogenic in causing not only cataract but global developmental delay and hepatic failure (Gillespie et al, 2014(Gillespie et al, , 2016Patel et al, 2016). These are termination of protein at Trp421, change of Ile312 to Thr and Leu232 to Pro.…”