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 non-syndromic 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.
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Acknowledgements
This study was supported by King Salman Center for Disability Research (FSA) and the National Eye Institute of the National Institutes of Health under Award Number R01EY021505 (SAL). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. SAL is a Pew Scholar in Biomedical Sciences.
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Figure S1. CYP51A1 is a novel candidate gene for syndromic cataract. (A) Pedigree for family 16DG0226. (B) Agile mapper ideogram reveals a single shared haplotype in the two affected (dark blue) that is not present in the unaffected individuals (pink) on Chr7. * Denotes a haplotype that is not unique to the affected individuals. (C) DNA sequence chromatogram of the missense mutation found in CYP51A1 that segregates within the family. Figure S2. TAPT1 is a novel candidate gene for isolated cataract. (A) Pedigree for family 12DG2657. (B) Agile mapper ideogram reveals a single locus on Chr4 (dark blue). (C) Genomic DNA sequence chromatogram of TAPT1 shows 1 bp insertion downstream of exon 6 that segregates with the family. (D) cDNA sequence chromatogram shows deletion of part of exon 5 and skipping of exon 6 in the aberrant band compared to the wild-type allele. Figure S3. RIC1 is a novel candidate gene for syndromic cataract. (A) Pedigree for two individual families with syndromic cataract. (B) Agile mapper ideogram reveals a locus for RIC1 on Chr9 (dark blue) (*denotes a haplotype that is not unique to the affected individuals). (C) Chromatogram of RIC1 shows missense change G>C that segregates with the family. Figure S4. TAF1A is a novel candidate gene for syndromic pediatric cataract. (A) Pedigree for family 11DG2176. (B) Sequence chromatogram for frameshift deletion mutation in TAF1A that segregates within the family. Figure S5. WDR87 is a novel candidate gene for pediatric cataract. (A) Pedigree for family 12DG2386. (B) Sequence chromatogram for stop-gain mutation in WDR87 that segregates within the family. Figure S6. Lens-expression curated PPI-network for non-syndromic cataract genes TAPT1 and RIC1 identifies candidates with known function or expression in the eye. (A, B) Integrated analysis-derived network using PPI data from String database (human interactions) and expression data from iSyTE E10.5 lens expression database identifies TAPT1 network with 22 direct connections and their interacting partners. Of these 22 interacting candidates, 15 are expressed in the lens, of which 7 are lens-enriched. iSyTE overlay identifies candidates with high lens expression such as SUCO, ANXA5, CALR. Proteins with known function in the lens, such as CDKN1A, CDKN1B, NOTCH1, SMAD3 are connected to direct partners of TAPT1 and are expressed in the network at E10.5. (C, D) Integrated analysis-derived network using PPI data from String database (human interactions) and lens expression identifies 39 direct interactors of RIC1, of which 32 candidates exhibit lens expression, and 14 are lens-enriched. GJA1, which is linked to microphthalmia and cataracts in humans is directly connected to RIC1 in the network. Color key represents high (deep red) to low (green) enrichment score and high (deep red) to low (white) expression scores. Genes absent in iSyTE are color-coded as grey. Figure S7. Lens-expression curated PPI-network for the syndromic cataract genes GEMIN4 and CYP51A1 identifies candidates with known function or expression in the eye. Integrated analysis-derived network using PPI data from String database (human interactions) and expression data from iSyTE E10.5 lens gene expression database identifies direct interacting proteins of GEMIN4 and CYP51A1. (A, B) GEMIN4 is connected to 53 protein-protein interacting partners, of which 50 candidates exhibit lens expression and 37 exhibit lens-enrichment. This analysis identifies a cluster of lens-expressed proteins such as GEMIN5, GEMIN6, GEMIN7, GEMIN8. (C, D) Network analysis demonstrates that CYP51A1 is directly connected to 51 interacting proteins, of which 35 candidates exhibit lens expression and 22 exhibit lens-enrichment. CYP51A1 is directly connected to ALDH1A1 and MAFG, both of which are linked to cataracts in mice. Several candidates for sterol biosynthetic process (GO:0016126) categories are enriched and expressed in the network. Color key represents high (deep red) to low (green) enrichment score and high (deep red) to low (white) expression scores. Genes absent in iSyTE are color-coded as grey. (PDF 3128 kb)
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Patel, N., Anand, D., Monies, D. et al. Novel phenotypes and loci identified through clinical genomics approaches to pediatric cataract. Hum Genet 136, 205–225 (2017). https://doi.org/10.1007/s00439-016-1747-6
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DOI: https://doi.org/10.1007/s00439-016-1747-6