ClinVar Genomic variation as it relates to human health

In 5 sibs (family GC4693) with retinal dystrophy, severe scoliosis, and hip dysplasia (SMDAX; 602271), Wheway et al. (2015) identified homozygosity for a c.218G-C transversion (c.218G-C, NM_004928.2) in the C21ORF2 gene, resulting in an arg73-to-pro (R73P) substitution at a highly conserved residue within a leucine-rich repeat (LRR) domain. Their unaffected mother was heterozygous for the mutation, which was present in the Exome Variant Server database at a minor allele frequency of 0 to 0.01% and in the ExAC database at 0.03304% (37/111,976 alleles). DNA was unavailable from their unaffected father. In 2 of the male sibs, splenomegaly and reduced sperm motility were also observed. In a brother and sister from an unrelated family from Northern Ireland (UCL-111) who exhibited narrow thorax and pelvic bone malformations on skeletal surveys and developed retinal degeneration in childhood, Wheway et al. (2015) identified compound heterozygosity for the R73P mutation and a c.671T-C transition in C21ORF2, resulting in a leu224-to-pro (L224P; 603191.0002) substitution. A third sib from family UCL-111 who also carried both mutations had only cone-rod dystrophy and did not show any skeletal anomalies. Exogenous expression of the R73P or L224P variant in mIMCD3 cells partially rescued ciliogenesis after siRNA knockdown of endogenous C21orf2, suggesting that they represent hypomorphic mutations. In addition, R73P mutant RNA rescued the nek1 (604588)-null zebrafish phenotype less effectively than wildtype C21ORF2, and the L224P mutant had little effect, confirming the hypomorphic effect of both variants. In a Turkish mother and son with SMDAX, and the mother's affected sister, as well as a 28-year-old Swedish woman, Wang et al. (2016) identified homozygosity for the R73P mutation in the C21ORF2 gene, located in the second LLR domain in the N-terminal conserved region. The mutation was absent in 100 Turkish controls, but was present in the ESP6500 and ExAC databases at very low allele frequencies (0.0154% and 0.0334%, respectively). Wang et al. (2016) stated that the skeletal phenotypes of the patients reported by Wheway et al. (2015) with the R73P mutation, who were studied as part of a Jeune syndrome (see 208500) cohort, were similar to their own axial SMD patients. In a 30-year-old woman with short stature, extremely narrow thorax, severe scoliosis, and retinal dystrophy, McInerney-Leo et al. (2017) identified homozygosity for the recurrent R73P mutation in the C21ORF2 gene. The authors stated that this patient exhibited features of both Jeune syndrome and axial SMD, and noted that the extent of her thoracic involvement appeared to be more severe than in other C21ORF2-associated cases. (less)