Severe intellectual disability in a patient with Burn–McKeown syndrome

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Burn–McKeown syndrome [BMKS (MIM: 608572)] is an ultra-rare autosomal-recessive condition, confirmed molecularly, to date, in 14 individuals (Wieczorek et al., 2014; Lüdecke and Wieczorek, 2016). BMKS was first described in 1992, and is characterized by eyelid defects, choanal atresia, variable degrees of hearing loss, cleft lip and/or palate, normal intellectual development, various cardiac defects, and typical facial dysmorphism, including narrow palpebral fissures, short philtrum, and large and protruding ears (Burn et al., 1992; Lüdecke and Wieczorek, 2016). Previously, we defined the molecular basis of BMKS as compound heterozygosity of low-frequency promoter deletions and rare loss-of-function mutations in TXNL4A were identified in a series of patients (MIM: 611595) (Wieczorek et al., 2014). TXNL4A encodes a highly conserved protein of the U5 spliceosomal complex (Liu et al., 2006; Lehalle et al., 2015). None of the patients reported to date with BMKS have learning difficulties (Wieczorek et al., 2014; Lüdecke and Wieczorek, 2016).
We report on a previously published patient with BMKS who, by the age of 9 years, presented with severe intellectual disability (Wieczorek et al., 2014). The patient [designated BMKS005 in the publication by Wieczorek et al. (2014)] was born at term to consanguineous parents after a pregnancy complicated by symmetrical intrauterine growth restriction. She was not exposed to any known teratogens prenatally. She has choanal atresia, cleft lip and palate, and bilateral sensorineural deafness. Brain MRI at the first year of age indicated one absent and one hypoplastic cochlear nerve and the patient was not eligible for a cochlear implant. She communicates by lip-reading and has limited sign language. She grows well, except for being relatively microcephalic (head circumference just below 0.4th percentile). She attends a special needs school and is taught by a teacher of the deaf on a one-to-one basis. She has significant difficulties in memory tasks, which impairs her learning. At 9 years of age, she does not know her age, her whole name, or time concepts. She has difficulties in learning sign language despite daily exposure; her expressive and receptive language skills have been markedly delayed throughout the school years. A cognitive assessment was carried out at the age of 7 years by an educational psychologist using the Leiter International Performance Scale-Revised (Leiter-R), a nonverbal cognitive assessment tool developed for individuals with communication challenges such as hearing impairment (Roid and Miller, 1997). Our patient had a brief IQ composite score of 51 (=0.1st percentile), indicating significantly impaired reasoning and problem-solving skills. The test was considered reliable in terms of concentration and motivation.
The screening test for intrauterine infections as well as standard metabolic tests including urine and plasma amino acids, urine organic acids, and lysosomal enzymes were normal. A standard karyotype was normal, as was chromosomal microarray analysis (at an average resolution of 180 kb, using OGT 8×60K array, analyzed by CytoSure Interpret, v3.4.3 software; Oxford Gene Technology (OGT), Oxfordshire, UK, Ensembl data Build, version 36). Whole-exome and genome sequencing identified that she had compound heterozygous variants in TXNL4A, confirming her BMKS diagnosis [methodology described in Wieczorek et al. (2014)]. No other clinically significant mutations were found. Her parents and siblings were healthy carriers of a heterozygous variant in TXNL4A. Whole-exome sequencing in the patient, her parents, and her siblings did not evidence any variant that could explain any developmental delay or intellectual disability.
BMKS is a condition previously unknown to affect intellectual development. The oldest individual reported has reached adulthood (age 34 years) without any evidence of intellectual disability (Wieczorek et al., 2014).
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