ClinVar Genomic variation as it relates to human health

In affected individuals from 8 families with Burn-McKeown syndrome (BMKS; 608572), including patients from 2 families originally reported by Burn et al. (1992) and the 2 German brothers reported by Wieczorek et al. (2003), Wieczorek et al. (2014) identified compound heterozygosity for a 34-bp deletion in the promoter of the TXNL4A gene (chr18:77,748,581-77,748,614del, GRCh37) and a truncating point mutation (611595.0002-611595.0004) or deletion involving TXNL4A (see, e.g., 611595.0005). In each family, the promoter deletion was present in heterozygosity in an unaffected parent. The promoter deletion was not found in the 1000 Genomes Project database; however, analysis of 3,165 population-based samples of German origin and 178 of South Asian origin revealed 45 heterozygous type 1 deletions and 1 homozygous type 1 deletion, for a German allele frequency of 0.76%. Haplotype analysis revealed that the promoter deletions were located on different haplotypes and thus most likely occurred due to recurrent events rather than a founder effect. In the family corresponding to cases 1 and 2 of Burn et al. (1992), the second mutation was a 1.235-Mb terminal deletion (del(18)(q23-qter): 76,841,645-78,077,248, GRCh37); an unrelated affected Vietnamese girl carried an almost identical 1.222-Mb deletion as her second mutation (del(18)(q23-qter): 76,854,774-78,077,248, GRCh37). In the female patient who was case 5 of Burn et al. (1992), the second mutation was a de novo 4.701-Mb terminal deletion on a ring chromosome 18 (46,XX,r(18)(p14q23)arr18q23: 73,376,178-78,077,248, GRCh37). Functional analysis in transfected HEK293 cells demonstrated that the wildtype promoter region enhanced luciferase expression 85-fold compared to control, whereas enhancer activity of the type 1 deletion was reduced by 59% compared to wildtype. Primer extension analysis provided further evidence that the deletion in the promoter region negatively affects transcription, since steady-state transcript levels of the allele carrying wildtype open reading frame (ORF) and the type 1 promoter deletion were reduced compared to transcript levels of the allele with mutant ORF and wildtype promoter. Wood et al. (2022) identified putative binding sites for 4 transcription factors (XBP1, 194355; c-JUN, see 165160; AHR/ARNT, see 600253; and ATF3, 603148) within a repeat of a 22-bp motif (RR2) in the 34-bp type 1 deletion region. Deletion of RR2 reduced promoter activity to 45% of wildtype, the same as deletion of the full 34-bp type 1 region. (less)