A variant in LMX1A causes autosomal recessive severe-to-profound hearing impairment

作者：Schrauwen Isabelle; Chakchouk Imen; Liaqat Khurram; Jan Abid; Nasir Abdul; Hussain Shabir; Nickerson Deborah A; Bamshad Michael J; Ullah Asmat; Ahmad Wasim; Leal Suzanne M^*

来源：Human Genetics, 2018, 137(6-7): 471-478.

DOI：10.1007/s00439-018-1899-7

• LMX1A
• Autosomal recessive hearing impairment
• Deafness
• Exome sequencing

Hereditary hearing impairment is a common sensory disorder that is genetically and phenotypically heterogeneous. In this study, we used a homozygosity mapping and exome sequencing strategy to study a consanguineous Pakistani family with autosomal recessive severe-to-profound hearing impairment. This led to the identification of a missense variant (p.Ile369Thr) in the LMX1A gene affecting a conserved residue in the C-terminus of the protein, which was predicted damaging by an in silico bioinformatics analysis. The p.Ile369Thr variant disrupts several C-terminal and homeodomain residue interactions, including an interaction with homeodomain residue p.Val241 that was previously found to be involved in autosomal dominant progressive HI. LIM-homeodomain factor Lmx1a is expressed in the inner ear through development, shows a progressive restriction to non-sensory epithelia, and is important in the separation of the sensory and non-sensory domains in the inner ear. Homozygous Lmx1a mutant mice (Dreher) are deaf with dysmorphic ears with an abnormal morphogenesis and fused and misshapen sensory organs; however, computed tomography performed on a hearing-impaired family member did not reveal any cochleovestibular malformations. Our results suggest that LMX1A is involved in both human autosomal recessive and dominant sensorineural hearing impairment.

• 出版日期2018-7