title: 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 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.
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: Nisha
authors.initials: N
authors.lastname: Patel
authors.affiliation: Department of Biological Sciences, University of Delaware, Newark, DE, 19716, USA.
authors.forename: Deepti
authors.initials: D
authors.lastname: Anand
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.|Saudi Human Genome Program, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia.
authors.forename: Dorota
authors.initials: D
authors.lastname: Monies
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: Sateesh
authors.initials: S
authors.lastname: Maddirevula
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.|Eye Institute, Cleveland Clinic Abu Dhabi, Abu Dhabi, United Arab Emirates.
authors.forename: Arif O
authors.initials: AO
authors.lastname: Khan
authors.affiliation: Department of Pediatrics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
authors.forename: Talal
authors.initials: T
authors.lastname: Algoufi
authors.affiliation: Department of Medical Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Alowain
authors.affiliation: Department of Pediatrics, King Fahad Medical City, Riyadh, Saudi Arabia.
authors.forename: Eissa
authors.initials: E
authors.lastname: Faqeih
authors.affiliation: Department of Pediatrics, King Khalid University Hospital and College of Medicine, King Saud University, Riyadh, Saudi Arabia.
authors.forename: Muneera
authors.initials: M
authors.lastname: Alshammari
authors.affiliation: Department of Medical Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Qudair
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: Hadeel
authors.initials: H
authors.lastname: Alsharif
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: Fatimah
authors.initials: F
authors.lastname: Aljubran
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: Hessa S
authors.initials: HS
authors.lastname: Alsaif
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: Niema
authors.initials: N
authors.lastname: Ibrahim
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: Firdous M
authors.initials: FM
authors.lastname: Abdulwahab
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: Mais
authors.initials: M
authors.lastname: Hashem
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: Haifa
authors.initials: H
authors.lastname: Alsedairy
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: Mohammed A
authors.initials: MA
authors.lastname: Aldahmesh
authors.affiliation: Department of Biological Sciences, University of Delaware, Newark, DE, 19716, USA.|Center for Bioinformatics and Computational Biology, University of Delaware, Newark, DE, 19716, USA.
authors.forename: Salil A
authors.initials: SA
authors.lastname: Lachke
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. falkuraya@kfshrc.edu.sa.|Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia. falkuraya@kfshrc.edu.sa.
authors.forename: Fowzan S
authors.initials: FS
authors.lastname: Alkuraya
mesh_terms: D000483:Alleles; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics; D002386:Cataract / Q000175:diagnosis* / Q000235:genetics*; D002648:Child; D002874:Chromosome Mapping; D002971:Cleft Lip / Q000235:genetics; D005786:Gene Expression Regulation; D056426:Genetic Loci; D023281:Genomics; D020662:Guanine Nucleotide Exchange Factors; D006720:Homozygote; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D008831:Microcephaly / Q000235:genetics; D010641:Phenotype; D035463:Pol1 Transcription Initiation Complex Proteins / Q000235:genetics; D025941:Protein Interaction Mapping; D017422:Sequence Analysis, DNA; D058886:Sterol 14-Demethylase / Q000235:genetics
chemical_list: C548418:CYP51A1 protein, human; D002352:Carrier Proteins; D020662:Guanine Nucleotide Exchange Factors; D008565:Membrane Proteins; D035463:Pol1 Transcription Initiation Complex Proteins; C505231:RIC1 protein, human; C091131:TAF1A protein, human; C519229:TAPT1 protein, mouse; C484259:Taf1a protein, mouse; D058886:Sterol 14-Demethylase