Deep analysis of the LRTOMTc.242G>A variant in non‐syndromic hearing loss North African patients and the Berber population: Implications for genetic diagnosis and genealogical studies

Abstract

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Current phenotypic and genetic spectrum of syndromic deafness in Tunisia: paving the way for precision auditory health

“…In one sibling (DF549-1 and 2) with WS2 (HI associated with iris heterochromia), no mutations in WS-associated genes have been detected, however, a homozygous missense variant c.242G>A; p.(Arg81Gln) has been identified in exon 7 of the LRTOMT gene. This is a founder mutation frequently associated with non-syndromic HI (DFNB63) in North Africa (Tunisia, Morocco, Libya) ( Ahmed et al, 2008 ; Charif et al, 2012 ; Mosrati et al, 2021 ; Souissi et al, 2021 ). To date, the LRTOMT gene has not been associated with a syndromic clinical entity.…”

Identification a novel pathogenic LRTOMT mutation in Mauritanian families with nonsyndromic deafness

“…Close to p.Leu60Pro variant, various changes in the same exon 7 were also associated with cases of moderate to profound congenital deafness making of this segment a mutation hot spot in the LRTOMT gene [10]. Besides the above homozygous c.242G>A (p.Arg81Gln) variant found in Tunisian, Libyan and Egyptian families [9,20] we may also cite missense variants c.122G>A (p.Arg41Gln), c.193T>C (p.Trp65Arg) in Morocco and Tunisia [11,12] and a nonsense mutation c.208C>T (p.Arg70*), in Tunisia [11,12,13] (Table 1). In this ethnic context, we noticed that all four affected families carrying the LRTOMT mutation (c.179T>C;p.(Leu60Pro) identified in this report belonged to the Moors (Maures), a predominant racial group of the Mauritanian population.…”

“…The wild type leucine residue was also located in an evolutionary highly conserved region [12] suggesting an important functional position of the residue (Fig 1B). Modeling, using WHATIF server (http://swift.cmbi.ru.nl) on rat COMT crystal structure as template for catechol-Omethyltransferase domain of the human LRTOMT2 (NM_001145309.4) showed that common LRTOMT variants associated with non-syndromic recessive hearing impairment led to hair cell degeneration process [9,11,20]. Close to p.Leu60Pro variant, various changes in the same exon 7 were also associated with cases of moderate to profound congenital deafness making of this segment a mutation hot spot in the LRTOMT gene [10].…”

“…However, a limitation of this study was that we have only screened exon 7 of LRTOMT. This screening only in exon 7 was mostly guided by very scarce findings of deafness associated variants in other exons reported by various studies in the region [9][10][11][12][13].…”

“…SNHI were related to about 134 identified causal genes with most cases passed down through variations in GJB2 gene with autosomal inheritance (Hereditary Hearing loss Home page: Last update August 2021). Several variations of LRTOMT gene, mostly in exon 7, have also been associated with deafness in different populations including cohorts from North African populations making of this gene the second most frequent, after GJB2, involved in congenital severe to profound hearing impairment [8,9,10,11,12,13]. In a previous work using Sanger sequencing of GJB2 gene, we have detected two pathogenic variants c.35delG (p.Gly12Valfs*2) and c.94C>T (p.Arg32Cys) in only 5 out of the 53 families with sporadic or hereditary deafness investigated [8].…”