ClinVar Genomic variation as it relates to human health

In 4 patients from 3 unrelated families with mitochondrial complex IV deficiency nuclear type 11 (MC4D11; 619054), Otero et al. (2019) identified compound heterozygous mutations in the COX20 gene: a c.41A-G transition, resulting in a lys14-to-arg (K14R) substitution, and a splice site mutation (c.157+3G-C; 614698.0003), resulting in a splicing abnormality and skipping of exon 2. The mutations, which were identified by whole-exome sequencing, segregated with disease in the families. Analysis of mRNA from fibroblasts from one of the patients (patient 1) showed expression of only a COX20 transcript consistent with absence of exon 2. No COX20 protein expression was detected in patient fibroblasts. In 2 sibs, aged 16 and 19 years, with MC4D11, Xu et al. (2019) identified compound heterozygous mutations in the COX20 gene: K14R and a c.222G-T transversion resulting in a trp74-to-cys (W74C; 614698.0004) substitution. The mutations, which were identified by whole-exome sequencing and confirmed by Sanger sequencing, segregated with disease in the family. Neither mutation was present in the 1000 Genomes Project database or in 200 healthy Chinese controls. A reduction of COX20 protein expression was detected in peripheral blood leukocytes from both sibs. In 3 unrelated Han Chinese patients (patients 1-3), one of whom was born to consanguineous parents, with MC4D11, Dong et al. (2021) identified homozygosity for the K14R mutation. The mutation was identified by a combination of homozygosity mapping and whole-exome sequencing and confirmed by Sanger sequencing. The parents were shown to be mutation carriers. Dong et al. (2021) analyzed cDNA from fibroblasts from patient 1 and showed that the c.41A-G transition affects splicing and leads to a frameshift and premature termination (Gly8ValfsTer2). COX20 protein expression was absent in patient fibroblasts. In 5 unrelated Han Chinese patients (patients 4-8) with MC4D11, Dong et al. (2021) identified compound heterozygosity for the K14R mutation and a second mutation in the COX20 gene: W74C (614698.0004) in patients 4 and 5; a c.98C-T transition resulting in a ser33-to-leu (S33L; 614698.0005) substitution in patient 6; a c.157+7A-G transition (614698.0006) in intron 2 resulting in a splicing abnormality in patient 7; and a c.259C-T transition resulting in a gln87-to-ter (Q87X; 614698.0007) substitution in patient 8. A minigene assay to determine the effects of the c.157+7A-G mutation showed that it caused skipping of exon 2, resulting in a frameshift and premature termination (Ser15ValfsTer11). The mutations, which were identified by whole-exome sequencing and confirmed by Sanger sequencing, segregated with disease in the families. The K14R mutation was present in the ChinaMAP database at a frequency of 0.00132 in the Chinese population and at a frequency of 0.00103 in the eastern Chinese population in an in-house exome database. In 3 unrelated Chinese patients (patients 1, 5, and 6) with MC4DN11, Ban et al. (2022) identified compound heterozygous mutations in the COX20 gene: the K14R mutation and a Q87X mutation (614698.0007). In 2 Chinese sibs (patients 3 and 4) with MC4DN11, Ban et al. (2022) identified compound heterozygous mutations in the COX20 gene: the K14R mutation and a splice site mutation (c.42+1G-A; 614698.0008) in intron 1, resulting in abnormal splicing. Neither parent carried the K14R mutation, but both carried the splice site mutation in heterozygous state. The splice site variant was not present in the gnomAD database. Analysis of RNA expression in patient fibroblasts demonstrated that both mutations affected the same splice site and resulted in a 20-bp deletion and frameshift at the 3-prime end of the cDNA of most COX20 transcripts. COX20 protein expression was also reduced. (less)