Novel missense and 3′-UTR splice site variants in LHFPL5 cause autosomal recessive nonsyndromic hearing impairment

Khurram Liaqat, Ilene Chiu, Kwanghyuk Lee, Imen Chakchouk, Paula B. Andrade-Elizondo, Regie Lyn P. Santos-Cortez, Shabir Hussain, Shoaib Nawaz, Muhammad Ansar, Muhammad Nasim Khan, Sulman Basit, Isabelle Schrauwen, Wasim Ahmad, Suzanne M. Leal

Research output: Contribution to journalArticlepeer-review

2 Scopus citations


LHFPL5, the gene for DFNB67, underlies autosomal recessive nonsyndromic hearing impairment. We identified seven Pakistani families that mapped to 6p21.31, which includes the LHFPL5 gene. Sanger sequencing of LHFPL5 using DNA samples from hearing impaired and unaffected members of these seven families identified four variants. Among the identified variants, two were novel: one missense c.452 G > T (p.Gly151Val) and one splice site variant (c.*16 + 1 G > A) were each identified in two families. Two known variants: c.250delC (p.Leu84*) and c.380 A > G (p.Tyr127Cys) were also observed in two families and a single family, respectively. Nucleotides c.452G and c.*16 + 1G and amino-acid residue p.Gly151 are under strong evolutionary conservation. In silico bioinformatics analyses predicted these variants to be damaging. The splice site variant (c.*16 + 1 G > A) is predicted to affect pre-mRNA splicing and a loss of the 5′ donor splice site in the 3′-untranslated region (3′-UTR). Further analysis supports the activation of a cryptic splice site approximately 357-bp downstream, leading to an extended 3′-UTR with additional regulatory motifs. In conclusion, we identified two novel variants in LHFPL5, including a unique 3′-UTR splice site variant that is predicted to impact pre-mRNA splicing and regulation through an extended 3′-UTR.

Original languageEnglish (US)
Pages (from-to)1099-1107
Number of pages9
JournalJournal of Human Genetics
Issue number11
StatePublished - Nov 1 2018

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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