Compound Heterozygosity of Low-Frequency Promoter Deletions and Rare Loss-of-Function Mutations in TXNL4A Causes Burn-McKeown Syndrome

Abstract

Mutations in components of the major spliceosome have been described in disorders with craniofacial anomalies, e.g., Nager syndrome and mandibulofacial dysostosis type Guion-Almeida. The U5 spliceosomal complex of eight highly conserved proteins is critical for pre-mRNA splicing. We identified biallelic mutations in TXNL4A, a member of this complex, in individuals with Burn-McKeown syndrome (BMKS). This rare condition is characterized by bilateral choanal atresia, hearing loss, cleft lip and/or palate, and other craniofacial dysmorphisms. Mutations were found in 9 of 11 affected families. In 8 families, affected individuals carried a rare loss-of-function mutation (nonsense, frameshift, or microdeletion) on one allele and a low-frequency 34 bp deletion (allele frequency 0.76%) in the core promoter region on the other allele. In a single highly consanguineous family, formerly diagnosed as oculo-oto-facial dysplasia, the four affected individuals were homozygous for a 34 bp promoter deletion, which differed from the promoter deletion in the other families. Reporter gene and in vivo assays showed that the promoter deletions led to reduced expression of TXNL4A. Depletion of TXNL4A (Dib1) in yeast demonstrated reduced assembly of the tri-snRNP complex. Our results indicate that BMKS is an autosomal-recessive condition, which is frequently caused by compound heterozygosity of low-frequency promoter deletions in combination with very rare loss-of-function mutations.

Homozygosity mapping and whole-genome sequencing reveals a deep intronic PROM1 mutation causing cone–rod dystrophy by pseudoexon activation

“…4 Panel-based sequencing of 105 retinal degenerationassociated genes and whole-genome sequencing, respectively, were performed as described before. 5,6 In-house automated data analysis pipeline and variant interpretation tools were used for variant calling.…”

A maternal deletion upstream of the imprint control region 2 in 11p15 causes loss of methylation and familial Beckwith–Wiedemann syndrome

“…15 Briefly, the library was prepared using PCR-free protocols (TruSeq DNA PCR-Free; Illumina) and sequencing was performed on the HiSeq2000/2500 systems (Illumina).…”

Sf3b4-depleted Xenopus embryos: A model to study the pathogenesis of craniofacial defects in Nager syndrome

“…During assembly of the U2 pre-spliceosomal complex, SAP49 binds to the pre-mRNA just upstream of the branch point sequence and plays a crucial role in tethering the U2 snRNP to the branch site during the splicing process (Champion-Arnaud and Reed, 1994). Mutations in genes encoding other components of the spliceosome, such as EFTUD2 (Lines et al, 2012), SNRPB (Lynch et al, 2014) and TXNL4A (Wieczorek et al, 2014) also cause craniofacial disorders, suggesting that defects in mRNA processing may underlie the etiology of some forms of MFD (Lehalle et al, 2015). …”