TXNL4A – Burn-McKeown syndrome

Burn-McKeown syndrome (BMKS) is a rare autosomal recessive craniofacial disorder characterized by choanal atresia, prominent ears, lower eyelid anomalies, cardiac defects, hearing loss, and cleft lip. BMKS arises from biallelic variants in TXNL4A, a component of the U5 spliceosomal snRNP. The disorder was first linked to TXNL4A in 2014 when compound heterozygosity of a core promoter 34-bp deletion and rare loss-of-function mutations was identified in affected families (PMID:25434003).

In an initial cohort, mutations were identified in 9 of 11 unrelated families (PMID:25434003). Affected individuals harbored a loss-of-function allele (nonsense, frameshift, or microdeletion) on one chromosome and a low-frequency 34-bp promoter deletion (allele frequency 0.76%) on the other. Additional case reports described homozygous promoter deletions in isolated choanal atresia and distinct promoter deletions segregating in consanguineous pedigrees (PMID:28905882; PMID:32187816).

The variant spectrum includes rare nonsense and frameshift mutations such as c.37C>T (p.Gln13Ter), splice-site variants (c.258-2A>G; c.258-3C>G), and promoter deletions (c.-222_-189del). Founder effects have been observed for the 34-bp promoter deletion in multiple populations. To date, ≥15 probands have been reported across diverse populations (PMID:25434003).

Segregation analysis in multiple multiplex families, including two siblings, two cousins, and a highly consanguineous pedigree with four affected members, supports autosomal recessive inheritance with at least six additional affected relatives.

Functional assays demonstrate that promoter deletions lead to reduced TXNL4A expression in reporter gene experiments and impaired tri-snRNP assembly in yeast models (PMID:25434003). Minigene splicing assays confirm exon skipping for splice-site variants, and dual-luciferase assays identify critical promoter motifs required for TXNL4A transcription (PMID:34713892).

These genetic and experimental data converge on haploinsufficiency of TXNL4A as the mechanism for BMKS. The consistent AR inheritance, robust segregation, and functional concordance support a strong gene–disease relationship. TXNL4A should be included in diagnostic panels for choanal atresia and craniofacial dysmorphisms to enable accurate diagnosis and genetic counseling.

Key Take-home: Pathogenic TXNL4A biallelic variants cause autosomal recessive Burn-McKeown syndrome, warranting molecular testing in individuals with choanal atresia and craniofacial anomalies.

References

• American journal of human genetics • 2014 • Compound heterozygosity of low-frequency promoter deletions and rare loss-of-function mutations in TXNL4A causes Burn-McKeown syndrome. PMID:25434003
• European Journal of Human Genetics • 2017 • Identification of causative variants in TXNL4A in Burn-McKeown syndrome and isolated choanal atresia. PMID:28905882
• Clinical genetics • 2022 • Expanding the genotypic spectrum of TXNL4A variants in Burn-McKeown syndrome. PMID:34713892

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