Novel Mutation in AIFM1 Gene Associated with X-Linked Deafness in a Moroccan Family.

INTRODUCTION: Auditory neuropathy is a hearing disorder where outer hair cell function within the cochlea is normal, but inner hair cell and/or the auditory nerve function is disrupted. It is a heterogeneous disorder, which can have either congenital or acquired causes. METHODS: We found a disease-segregating mutation in the X-linked AIFM1 gene through whole-exome sequencing, encoding the apoptosis-inducing factor mitochondrion-associated 1. RESULTS: The impact of the c.1045A>G; p.(Ser349Gly) mutation on the AIFM1 protein was predicted using different bioinformatics tools. The pedigree analysis in the examined family was consistent with X-linked dominant inheritance. DISCUSSION/CONCLUSION: To our knowledge, this is the first study that identifies a mutation in the AIFM1 gene in Moroccan patients suffering from X-linked auditory neuropathy.

Two novel homozygous missense mutations identified in the BSND gene in Moroccan patients with Bartter's syndrome.

OBJECTIVES: Hearing loss (HL) is one of the most common sensorineural disorders. In the present study, we identified two novel missense mutations in BSND gene causing Bartter syndrome type IV which is a genetic disease with an autosomal recessive transmission, characterized by hypokalaemia, metabolic alkalosis, an elevation in plasma renin activity and hyperaldosteronism as well as sensorineural deafness. METHODS: Whole-exome sequencing was performed to study the genetic causes of Hearing loss in two unrelated patients from two Moroccan families. RESULTS: The two novel homozygous mutations p.Arg8Gly (c.22C > G), p.Thr36Asn (c.107C > A) in exon 1 of BSND gene which encodes barttin were identified in 7 patients belonging to two unrelated families originated from central region of Morocco. CONCLUSION: We identified two novel missense mutations p.Arg8Gly and p.Thr36Asn in exon 1 of BSND gene; both mutations were described for the first time in Moroccan patients with Bartter syndrome type IV.

A novel mutation in SLITRK6 causes deafness and myopia in a Moroccan family.

Deafness and myopia syndrome is characterized by moderate-profound, bilateral, congenital or prelingual deafness and high myopia. Autosomal recessive non-syndromic hearing loss is one of the most prevalent human genetic sensorineural defects. Myopia is by far the most common human eye disorder that is known to have a clear heritable component. The analysis of the two exons of SLITRK6 gene in a Moroccan family allowed us to identify a novel single deleterious mutation c.696delG, p.Trp232Cysfs*10 at homozygous state in the exon 2 of the SLITRK6, a gene reported to cause deafness and myopia in various populations.

Homozygous mutations in PJVK and MYO15A genes associated with non-syndromic hearing loss in Moroccan families.

OBJECTIVES: Autosomal recessive non-syndromic hearing loss is a heterogeneous disorder and the most prevalent human genetic sensorineural defect. In this study, we investigated the geneticcause of sensorineural hearing loss in Moroccan patients and presented the importance of whole exome sequencing (WES) to identify candidate genes in two Moroccan families with profound deafness. METHODS: After excluding mutations previously reported in Moroccan deaf patients, whole exome sequencing was performed and Sanger sequencing was used to validate mutations in these genes. RESULTS: Our results disclosed the c.113_114insT (p.Lys41GlufsX8) and c.406C > T (p.Arg130X) homozygous mutations in PJVK and a homozygous c.5203C > T (p.Arg1735Trp) mutation in MYO15A, both genes responsible for non-syndromic recessive hearing loss DFNB59 and DFNB3, respectively. CONCLUSION: We identified in Moroccan deaf patients two mutations in PJVK and one mutation in MYO15A described for the first time in association with non-syndromic recessive hearing loss. These results emphasize that whole exome sequencing is a powerful diagnostic strategy to identify pathogenic mutations in heterogeneous disorders with many various causative genes.

Update of the spectrum of GJB2 gene mutations in 152 Moroccan families with autosomal recessive nonsyndromic hearing loss.

Deafness is one of the most common genetic diseases in humans and is subject to important genetic heterogeneity. The most common cause of non syndromic hearing loss (NSHL) is mutations in the GJB2 gene. This study aims to update and evaluate the spectrum of GJB2 allele variants in 152 Moroccan multiplex families with non syndromic hearing loss. Seven different mutations were detected: c.35delG, p.V37I, p.E47X, p.G200R, p.Del120E, p.R75Q, the last three mutations were described for the first time in Moroccan deaf patients, in addition to a novel nonsense mutation, the c.385G>T which is not referenced in any database. Sixty six families (43.42%) have mutations in the coding region of GJB2, while the homozygous c.35delG mutation still to date the most represented 51/152 (33.55%). The analysis of the geographical distribution of mutations located in GJB2 gene showed more allelic heterogeneity in the north and center compared to the south of Morocco. Our results showed that the GJB2 gene is a major contributor to non syndromic hearing loss in Morocco. Thus, this report of the GJB2 mutations spectrum all over Morocco has an important implication for establishing a suitable molecular diagnosis.

A novel mutation of AFG3L2 might cause dominant optic atrophy in patients with mild intellectual disability.

Dominant optic neuropathies causing fiber loss in the optic nerve are among the most frequent inherited mitochondrial diseases. In most genetically resolved cases, the disease is associated to a mutation in OPA1, which encodes an inner mitochondrial dynamin involved in network fusion, cristae structure and mitochondrial genome maintenance. OPA1 cleavage is regulated by two m-AAA proteases, SPG7 and AFG3L2, which are, respectively involved in Spastic Paraplegia 7 and Spino-Cerebellar Ataxia 28. Here, we identified a novel mutation c.1402C>T in AFG3L2, modifying the arginine 468 in cysteine in an evolutionary highly conserved arginine-finger motif, in a family with optic atrophy and mild intellectual disability. Ophthalmic examinations disclosed a loss of retinal nerve fibers on the temporal and nasal sides of the optic disk and a red-green dyschromatopsia. Thus, our results suggest that neuro-ophthalmological symptom as optic atrophy might be associated with AFG3L2 mutations, and should prompt the screening of this gene in patients with isolated and syndromic inherited optic neuropathies.

Recessive TBC1D24 Mutations Are Frequent in Moroccan Non-Syndromic Hearing Loss Pedigrees.

Mutations in the TBC1D24 gene are responsible for four neurological presentations: infantile epileptic encephalopathy, infantile myoclonic epilepsy, DOORS (deafness, onychodystrophy, osteodystrophy, mental retardation and seizures) and NSHL (non-syndromic hearing loss). For the latter, two recessive (DFNB86) and one dominant (DFNA65) mutations have so far been identified in consanguineous Pakistani and European/Chinese families, respectively. Here we report the results of a genetic study performed on a large Moroccan cohort of deaf patients that identified three families with compound heterozygote mutations in TBC1D24. Four novel mutations were identified, among which, one c.641G>A (p.Arg214His) was present in the three families, and has a frequency of 2% in control Moroccan population with normal hearing, suggesting that it acts as an hypomorphic variant leading to restricted deafness when combined with another recessive severe mutation. Altogether, our results show that mutations in TBC1D24 gene are a frequent cause (>2%) of NSHL in Morocco, and that due to its possible compound heterozygote recessive transmission, this gene should be further considered and screened in other deaf cohorts.