ClinVar Genomic variation as it relates to human health

In 4 affected individuals from 3 unrelated French Canadian families with gastrointestinal defects and immunodeficiency syndrome-1 (GIDID1; 243150), Samuels et al. (2013) identified homozygosity for a 4-bp deletion (c.53344_53347delAAGT) at the splice donor site of exon 7 of the TTC7A gene. The deletion was found in heterozygosity in both parents from each family, as well as both parents from 2 more French Canadian families in which DNA was unavailable from the deceased affected children. Unaffected sibs in these families were either heterozygous for the deletion or did not carry it at all. Sequencing of the cDNA product from patient RNA revealed that exon 7 was skipped, with splicing of exon 6 directly to exon 8; this aberrant splicing generated a 158-bp deletion in the resulting cDNA, predicted to cause a frameshift with 49 new amino acids followed by a termination codon. In human lymphocyte RNA sequencing data from other unrelated projects, Samuels et al. (2013) found rare examples of reads skipping exon 7, with 4 of 880 reads excluding exon 7; they suggested that exon 7 inclusion may be intrinsically variable even with a wildtype splice donor site. In 2 affected sibs from a seventh French Canadian family, Samuels et al. (2013) identified compound heterozygosity for the 4-bp deletion and a c.13307A-G transition in exon 20 of the TTC7A gene, resulting in a leu823-to-pro (L823P; 609332.0002) substitution at a highly conserved residue in the carboxy terminus. The authors concluded that the 4-bp deletion represents a founder mutation in the French Canadian population, with the L823P missense mutation having arisen more recently or being derived from a British or Scottish population. In a 2-year-old boy (patient F5-A) with combined immunodeficiency and multiple intestinal atresia, Chen et al. (2013) identified compound heterozygosity for the 4-bp deletion, which they designated c.1000_1003delAAGT (chr2.47,221,651delAAGT, GRCh37) and 2 deleterious single-nucleotide variants on the other allele of the TTC7A gene (609332.0008). The patient inherited the 4-bp deletion from his unaffected French Canadian father. Quantitative RT-PCR of patient fibroblasts showed reduced expression of TTC7A, to 54% of control levels, and confirmed that the 4-bp deletion causes skipping of exon 7. (less)