Abstract
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 1Δ) 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 1Δ 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 2Δ)). 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.
Highlights
Burn-McKeown syndrome (BMKS) was first described in five children by Burn et al.[1]
By testing the expected autosomal dominant disease model, we identified a novel splice site variant upstream of the last exon in TXNL4A (c.258-2A4G, (p.?)), that was inherited from the father
whole-genome sequencing (WGS) data indicated that both parents each carried a different sequence change within the 3′ UTR of TXNL4A that was not inherited by their daughter: the father was heterozygous for hg[19] chr18:g.77733297dupC and the mother for hg[19] chr18:g.77733273C4T
Summary
Burn-McKeown syndrome (BMKS) was first described in five children by Burn et al.[1]. It is a rare disorder characterized by choanal atresia, prominent ears, hypertelorism with short palpebral fissures and abnormalities of the outer third of the lower eyelids. Other features that can be observed are structural cardiac abnormalities, conductive and sensorineural hearing loss, and unilateral cleft lip.[1] There is clinical overlap with both Treacher Collins and CHARGE syndromes. As the syndrome was repeatedly described in siblings and mainly in males, an autosomal recessive[1] or X-linked inheritance pattern was suggested.[2] the identification of a chromosomal rearrangement, 46,XX,r(18)(p14q23), in an isolated female case with features of BMKS suggested terminal 18p or 18q as the locus for the disorder.[1] This was borne out by the detection of causative compound heterozygous variants in TXNL4A (located on chromosome 18q23), identified more than 20 years after the initial description of BMKS.[3]
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