Homozygosity mapping identifies a GALK1 mutation as the cause of autosomal recessive congenital cataracts in 4 adult siblings

• Published in: Gene Vol. 534; no. 2; pp. 218 - 221
• Main Authors: Chacon-Camacho, Oscar F., Buentello-Volante, Beatriz, Velázquez-Montoya, Roberto, Ayala-Ramirez, Raul, Zenteno, Juan C.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 25.01.2014
• Subjects: adults; Aged; Cataract; Cataract - congenital; Cataract - genetics; Chromosome Mapping - methods; DNA Mutational Analysis - methods; etiology; Eye; eyes; Female; Galactokinase - deficiency; Galactokinase - genetics; Galactosemia; GALK1; genes; Genes, Recessive; Genetic Linkage - genetics; Genome-Wide Association Study - methods; genotype-phenotype correlation; homozygosity; Homozygosity mapping; Homozygote; Humans; infancy; Male; microarray technology; Middle Aged; Mutation; Pathology, Molecular - methods; patients; Pedigree; polymerase chain reaction; Retrospective Studies; sequence analysis; Siblings; single nucleotide polymorphism; surgery; Cataract; C; GALT; Homozygosity mapping; OMIM; Galactosemia; Q; GALE; BRLMM; T; Mb; DNA; SNPs; Ng; PCR; GALK1; On line Mendelian Inheritance in Man; glutamine; galactose-1-phosphate uridyltransferase; cytosine; desoxyribonucleic acid; single nucleotide polymorphisms; UDP-galactose-4′-epimerase; polymerase chain reaction; galactokinase; nanogram; Bayesian Robust Linear Model with Mahalanobis distance classifier; megabase; thymine
• ISSN: 0378-1119; 1879-0038; 1879-0038
• DOI: 10.1016/j.gene.2013.10.057

Monogenic congenital cataract is one of the most genetically heterogeneous ocular conditions with almost 30 different genes involved in its etiology. In adult patients, genotype–phenotype correlations are troubled by eye surgery during infancy and/or long-term ocular complications. Here, we describe the molecular diagnosis of GALK1 deficiency as the cause of autosomal recessive congenital cataract in a family from Costa Rica. Four affected siblings were included in the study. All of them underwent eye surgery during the first decade but medical records were not available. Congenital cataract was diagnosed by report. Molecular analysis included genome wide homozygosity mapping using a 250K SNP Affymetrix microarray followed by PCR amplification and direct nucleotide sequencing of candidate gene. Genome wide homozygosity mapping revealed a 6Mb region of homozygosity shared by two affected siblings at 17q25. The GALK1 gene was included in this interval and direct sequencing of this gene revealed a homozygous c.1144C>T mutation (p.Q382*) in all four affected subjects. This work demonstrates the utility of homozygosity mapping in the retrospective diagnosis of a family with congenital cataracts in which ocular surgery at early age, the lack of medical records, and the presence of long term eye complications, impeded a clear clinical diagnosis during the initial phases of evaluation. •A genomic analysis approach was used to unravel the genetic cause of an eye disease.•Homozygosity mapping with SNP microarrays was performed.•A retrospective diagnosis of GALK1-associated cataracts was made in a family.