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Purpose: To investigate the molecular basis of retinitis pigmentosa in two consanguineous families of Pakistani origin with multiple affected members., Methods: Homozygosity mapping and Sanger sequencing of candidate genes were performed in one family while the other was analyzed with whole exome next-generation sequencing. A minigene splicing assay was used to confirm the splicing defects., Results: In family MA48, a novel homozygous nucleotide substitution in C8orf37, c.244-2A>C, that disrupted the consensus splice acceptor site of exon 3 was found. The minigene splicing assay revealed that this mutation activated a cryptic splice site within exon 3, causing a 22 bp deletion in the transcript that is predicted to lead to a frameshift followed by premature protein truncation. In family MA13, a novel homozygous null mutation in C8orf37, c.555G>A, p.W185*, was identified. Both mutations segregated with the disease phenotype as expected in a recessive manner and were absent in 8,244 unrelated individuals of South Asian origin., Conclusions: In this report, we describe C8orf37 mutations that cause retinal dystrophy in two families of Pakistani origin, contributing further data on the phenotype and the spectrum of mutations in this form of retinitis pigmentosa.

Purpose: To investigate whether three consanguineous families from the Punjab province of Pakistan, with affected members with recessively inherited congenital cataract microcornea with corneal opacity, are genetically homogeneous., Methods: An ophthalmic examination was performed on each family member to establish the diagnosis. The two largest families were analyzed by homozygosity mapping using SNP arrays. Linkage was confirmed using polymorphic microsatellite markers, and logarithm of odds (LOD) scores were calculated. Candidate genes were prioritized using the ENDEAVOUR program., Results: Autosomal recessive congenital cataract-microcornea with corneal opacity mapped to chromosome 10cen for family MEP57 and to either chromosomes 2ptel or 20p for family MEP60. For MEP57, the refined interval was 36.8 Mb flanked by D10S1208 (35.3 Mb) and D10S676 (72.1 Mb). For MEP60, the interval containing the mutation was either 6.7 Mb from the telomere of chromosome 2 to marker D2S281 or 3.8 Mb flanked by D20S906 (1.5 Mb) and D20S835 (5.3 Mb). Maximum multipoint LOD scores of 3.09, 1.94, and 3.09 were calculated at D10S567, D2S281, and D20S473 for families MEP57 and MEP60. Linkage to these loci was excluded for family MEP68. SLC4A11 was excluded as a candidate gene for the observed phenotype in MEP60., Conclusions: The authors have identified two new loci, one on chromosome 10cen and the other on 2ptel or 20p, that are associated with recessively inherited congenital cataract-microcornea with corneal opacity. This phenotype is genetically heterogeneous in the Pakistani population. Further genetic studies of this kind, combined with a detailed phenotypic description, will contribute to more precise classification criteria for anterior segment disease.