Abstract
BackgroundConsanguinity is an important risk factor for autosomal recessive (AR) disorders. Extended genomic regions identical by descent (IBD) in the offspring of consanguineous parents give rise to recessive disorders with identical (homozygous) pathogenic variants in both alleles. However, many clinical phenotypes presenting in the offspring of consanguineous couples are still of unknown etiology. Nowadays advances in High Throughput Sequencing provide an excellent opportunity to achieve a molecular diagnosis or to identify novel candidate genes.ResultsTo exploit all available information from the family structure we developed CATCH, an algorithm that combines genotyped SNPs of all family members for the optimal detection of Runs Of Homozygosity (ROH) and exome sequencing data from one affected individual to identify putative causative variants in consanguineous families.ConclusionsCATCH proved to be effective in discovering known or putative new causative variants in 43 out of 50 consanguineous families. Among them, novel variants causative of familial thrombocytopenia, sclerosis bone dysplasia and the first homozygous loss-of-function mutation in FGFR3 in human causing severe skeletal deformities, tall stature and hearing impairment were identified.Electronic supplementary materialThe online version of this article (doi:10.1186/s12859-015-0727-5) contains supplementary material, which is available to authorized users.
Highlights
Consanguinity is an important risk factor for autosomal recessive (AR) disorders
Input CATCH takes as input: 1) the variants packaged in the standard Variant Calling Format (VCF) for one affected individual of the family; 2) a PED formatted file describing the pedigree structure and the genotypes of all informative members of the family; and 3) ROH (Runs Of Homozygosity) regions as calculated by PLINK from the PED file and SNP arrays data
All samples were genotyped with a dense SNP array (HumanOmniExpress Bead Chip by Illumina) to identify Runs of Homozygosity and exome sequencing on the Illumina HiSeq2000 was performed on one affected individual per family
Summary
CATCH has been employed on processed samples collected from 50 consanguineous families suggestive of AR of inheritance and a wide spectrum of AR phenotypes [10]. ROHs were calculated by PLINK as stretches of 50 homozygous consecutive SNPs irrespective of the total length of the genomic region, allowing for one mismatch We considered this as a reasonable trade-off between catching a significant amount of ROH (Additional file 1: Figure S1) and limiting the number of small IBS regions that are common in all individuals. CATCH identified the first homozygous loss-offunction (predicted) mutation in FGFR3 in human [19] This gene is one of many physiological regulators of linear bone growth and normally functions as an inhibitor, acting negatively on both proliferation and terminal differentiation of growth plate chondrocytes [20]. Before this finding, all pathogenic FGFR3 mutations in humans were associated with constitutive FGFR3 activation by impairing endochondral bone growth
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