Identification of mutations in TXNL4A in Burn-McKeown Syndrome and isolated choanal atresia

Burn-McKeown syndrome (BMKS) is a rare syndrome characterized by choanal atresia, prominent ears, abnormalities of the outer third of the lower eyelids, cardiac abnormalities, hearing loss, and unilateral cleft lip. Recently, compound heterozygous mutations were identified in TXNL4A. We analyzed a subject with clinical features of BMKS and her parents by whole genome sequencing and also identified compound heterozygous mutations in TXNL4 (a novel splice site mutation (c.258-2A&gt;G, p.?) and a 34 bp type 1Δ promoter deletion (c.-222_-189del34, p.?) in the proband). Subsequently, we tested a cohort of 16 subjects with clinical features of BMKS and 15 subjects with isolated choanal atresia for mutations in TXNL4A by dideoxy-sequence analysis. In one individual with BMKS unrelated to the first family, we identified the identical compound heterozygous mutations. In an individual with isolated choanal atresia, we found homozygosity for the same type 1Δ promoter deletion, whilst in two cousins from a family with choanal atresia and other minor anomalies we found homozygosity for a different deletion (type 2Δ) within the promoter. Hence, we identified recessive mutations in TXNL4A in 2 subjects with BMKS, but also in 3 patients (2 families) with isolated choanal atresia.</p

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Burn-McKeown syndrome (BMKS) is a rare syndrome characterized by choanal atresia, prominent ears, abnormalities of the outer third of the lower eyelid, structural cardiac abnormalities, conductive and sensorineural hearing loss, and cleft lip. Recently, causative compound heterozygous variants were identified in TXNL4A. We analyzed an individual with clinical features of BMKS and her parents by whole-genome sequencing and identified compound heterozygous variants in TXNL4A (a novel splice site variant (c.258-2A>G, (p.?)) and a 34 bp promoter deletion (hg19 chr18:g.77748581_77748614del (type 1Delta) in the proband). Subsequently, we tested a cohort of 19 individuals with (mild) features of BMKS and 17 individuals with isolated choanal atresia for causative variants in TXNL4A by dideoxy-sequence analysis. In one individual with BMKS unrelated to the first family, we identified the identical compound heterozygous variants. In an individual with isolated choanal atresia, we found homozygosity for the same type 1Delta promoter deletion, whilst in two cousins from a family with choanal atresia and other minor anomalies we found homozygosity for a different deletion within the promoter (hg19 chr18: g.77748604_77748637del (type 2Delta)). Hence, we identified causative recessive variants in TXNL4A in two individuals with BMKS as well as in three individuals (from two families) with isolated choanal atresia