Unrelated Tunisian Families Research Articles

Tremor Ataxia With Central Hypomyelation Phenotype Related to a Recurrent POLR3A Mutation in Six Unrelated Tunisian Families.

POLIII-related leukodystrophies are a group of recently recognized hereditary white matter diseases with a similar clinical and radiological phenotype. No Tunisian studies have been published about POLIII-related leukodystrophy due to POLR3A variants. The aim of this study was to contribute to the clinical, radiological, and genetic characterization of POLR3A-related leukodystrophy in a Tunisian cohort. We report six cases of genetically confirmed POLR3A-related leukodystrophy belonging to six unrelated Tunisian families, along with a review of previously published pediatric cases. All patients were born to consanguineous marriages and originated from the North or the Center of Tunisia. Age at onset varied between 15 months and 6 years. The clinical phenotype was similar in all patients with cerebellar ataxia, tremor, and nystagmus being the key features. Brain imaging showed diffuse hypomyelination in all patients with progressive cerebellar atrophy in three patients. Molecular analysis identified the same bi-allelic NM_007055.4:c.2011T>C; p.(Trp671Arg) variant in the POLR3A gene in all patients. We hypothesize a founder effect for the identified variant given its recurrence in six unrelated individuals with a similar clinical phenotype. Given the apparent genetic homogeneity of Tunisian POLR3A patients, the recurrent variant should be directly targeted. This should facilitate diagnosis in index patients, and genetic counseling.

Analysis of ProP1 Gene in a Cohort of Tunisian Patients with Congenital Combined Pituitary Hormone Deficiency.

Background: Non-syndromic combined pituitary hormone deficiency (CPHD) occurs due to defects in transcription factors that govern early pituitary development and the specification of hormone-producing cells. The most common mutations are in the Prophet of Pit-1 (ProP1) gene. This work aims to (1) report findings of genetic analyses of Tunisian patients with non-syndromic CPHD and (2) describe their phenotype patterns and their evolution through life. Methods: Fifteen patients from twelve unrelated families with variable clinical phenotypes were included after excluding autoimmune and acquired forms of non-syndromic CPHD. Detailed pedigree charts and auxological, hormonal, radiological, and therapeutic details were recorded. Sanger sequencing was performed, and sequences were analyzed with a specific focus on coding and splice site regions of the ProP1 gene. Retained variants were classified using several in silico pathogenicity prediction tools and the VarSome platform. Results: We identified the common p.Arg73Cys mutation in seven patients from four unrelated pedigrees. We found a novel homozygous mutation (c.340C>T) in one sporadic case. This mutation generates a truncated ProP1 protein, predicted to be non-functional, lacking the last 112 codons (p.(Gln114Ter)). We confirmed by polymerase chain reaction (PCR) the absence of large exon deletions or insertions in the remaining sporadic patients (7/8). Conclusions: We report two mutations {one newly identified [p.(Gln114Ter)] and one previously reported (p.Arg73Cys)} in five unrelated Tunisian families with non-syndromic CPHD. This work is of clinical importance as it reports the high frequency of the p.Arg73Cys mutation in Tunisian CPHD families. Our study also illuminated the involvement of novel gene(s) in the emergence of non-syndromic CPHD.

213 Genetic study of the largest Tunisian cohort of 15 patients with Netherton syndrome: Two new SPINK5 mutations and founder effect

Several pathogenic mutations have been identified in the SPINK5 gene encoding kazal-type serine protease inhibitors (LEKTI) involved in the regulation of skin barrier formation resulting in Netherton syndrome NS. Our work aims to study the clinical, histological and genetic characteristics of Tunisian patients with NS. We investigated 15 patients with NS from 12 unrelated Tunisian families, referred to our department for genetic confirmation of their diagnosis. Clinical examination at birth showed non-bullous congenital ichthyosiform erythroderma (EIC) in 14 patients, bullous in only one.

X-linked recessive ichthyosis in 8 Tunisian patients: awareness of misdiagnosis due to the technical trap of the STS pseudogene

IntroductionX-linked recessive ichthyosis (XLI) is a genodermatosis, caused by a deficiency of the steroid sulphatase enzyme encoded by the STS gene (OMIM # 300,747). Adopted XLI molecular diagnosis approaches differ from one laboratory to another depending on available technical facilities. Our work aims to figure out a sound diagnostic strategy for XLI.Patients and methodsWe collected 8 patients with XLI, all males, from 3 unrelated Tunisian families from central Tunisia. Genetic diagnosis was conducted through a large panel of genetic techniques including: Sanger Sequencing, haplotype analysis of STR markers, MLPA analysis, FISH and array CGH.ResultsDirect Sanger sequencing of the STS gene showed the same deletion of 13 base pairs within the exon 4 in all patients resulting in a premature stop codon. However, all patients’ mothers were not carriers of this variant and no common haplotype flanking STS gene was shared between affected patients. Sequence alignment with reference human genome revealed an unprocessed pseudogene of the STS gene located on the Y chromosome, on which the 13 bp deletion was actually located. STS MLPA analysis identified a deletion of the entire STS gene on X chromosome for all affected patients. This deletion was confirmed by FISH and delineated by array CGH.ConclusionAll our patients shared a deletion of the entire STS gene revealed by MLPA, confirmed by FISH and improved by array CGH. Geneticists must be aware of the presence of pseudogenes that can lead to XLI genetic misdiagnosis.

PS1106 A RETROSPECTIVE ANALYSIS OF IMMUNE THROMBOCYTOPENIA PATIENTS TREATMENT RESULTS AFTER SEQUENTIAL SWITCHING OF THROMBOPOIETIC RECEPTOR‐AGONISTS

Background:Immune thrombocytopenia (ITP) is an immune‐mediated disease characterized by increased platelet destruction and impaired platelet production with transient or persistent decrease in the platelet count and increased risk of bleeding. Romiplostim (R) and Eltrombopag (E) are the first thrombopoietic receptor‐agonists (TPO‐ra) with demonstrated efficacy against ITP. So far, very few data are available about the potential contribution of switching from romiplostim to eltrombopag or vice versa in terms of efficacy or tolerance.Aims:To evaluate the reasons for and result of TPO‐ra switching in adult ITP patientsMethods:We retrospectively analyzed all patients who received sequential treatment with both TPO‐RA between 2014 and 2018 in Moscow city hematology center (Botkin hospital).Results:Thirty‐three pts with primary ITP were included; 19 received first Romiplostim and 15 received first Eltrombopag. Reasons for switching were inefficacy (n = 30) and adverse events (n = 3). All patients (33) had previously received multiple courses of corticosteroids and IV Ig infusions, four (10%) received immunosuppression (rituximab), and five (14%) performed splenectomy. The median platelet count at the administration of the second TPO‐ra was 17x109/l (range 3–25x109/l). Twenty‐five (76%) patients had bleeding symptoms before the second TPO‐ra administration.From 33 included patients partial response (> 50x109/l without platelet transfusions and bleeding) was achieved in 16 (70%). PR was seen in sixteen from 19 (84%) in E to R group and seven from 15 (47%) in R to E group. Complete response (>100x109/l without pl. transfusions and bleeding) were achieve in 17 from 33 (52%). Twelve pts from 19 (63%) achieve CR in E to R group and five from 15 (30%) in R to E group. Two of 17 (10%) pts achieved a CR within 1–3 months, 11 (67%) pts in 3–12 months, and four (23%) pts later than 1 year from the start of switching to second TPO‐ra therapy.Three pts (2 in E group due to repeated thrombosis, and 1 in R group due to persistent increased liver enzymes) with recommendation of switching to second TPO‐ra due to adverse events resolved rapidly and maintained remission on alternative drug.In nine pts (28%) the switching to second TPO‐ra therapy was ineffective (blood platelet level was less than 30x109/l pl). All of them were resistant to first TPO‐ra.Summary/Conclusion:Our results confirmed that switching from one thrombopoietic receptor‐agonist to another could be beneficial for patients with chronic immune thrombopenia who failed to respond. Yet longer follow‐up and larger number of pts enrolled are required to fully assess the potential benefits of such therapy change.

PS1105 CONGENITAL DEFICIENCY OF COAGULATION FACTOR VII IN THE SOUTH OF TUNISIA: ABOUT 88 CASES

Background:Congenital factor VII deficiency (FVII) is the least rare among uncommon hereditary bleeding disorders (1:500 000). This coagulopathy, inherited in an autosomal recessive pattern, is characterized by a bleeding tendency, varied prognosis and a lack of correlation between clinical phenotypes and biological analysis.Aims:The objective of our study was to describe and to explore the clinical and the biological features of FVII deficiency in the South of Tunisia.Methods:Our FVII‐deficient cohort consisted of 88 patients whose FVII activity was less than 50% and who were referred to our laboratory from January 2000 to December 2018 because of a prolonged prothrombin time (PT) or hemorrhagic manifestations. The FVII deficiency was considered as severe for FVII coagulant activities (FVII:C) <2%, moderate for rates between 2 and 19% and minor for values between 20 and 49%. The statistical analysis was based on Chi‐squared test.Results:The mean age of the patients was 22 years old ranging between 21 months and 63 years old and the sex ratio was about 0.83. Among 88 patients, belonging to 58 unrelated Tunisian families, 45 cases (51.2%) were diagnosed accidentally during presurgical screening, 28 cases (31.8%) were noticed following family screening and 15 patients (17%) were discovered due to bleeding accidents. Clinically, 64 patients (72.7%) were asymptomatic whereas the bleeding frequency was about 27.3%. Clinical examination revealed several bleeding manifestations as follows : gingivorrhagia noticed in 12 patients (50%), followed by epistaxis in nine patients (37.5%). Four cases had hematemesis (16.6%), hematoma was found in three (12.5%) and one of the patients had a cerebral haemorrhage (4.2%). Added to that, some bleeding signs, not commonly related to the FVII deficiency, had been noticed such as: menorrhagia, haemoperitoneum, hematuria and bruising. The laboratory severity of each patient was also determined : FVII deficiency was classified as severe in 3.4%, moderate in 14.8% and minor in 81.8% of cases. With reference to statistics, results showed a weak correlation between clinical data and biological levels of FVII:C (p = 0.004). In fact, 15 patients with a minor FVII deficiency had presented haemorrhages with a variable bleeding severity; while one of the patients was asymptomatic despite the severity of his defect.Summary/Conclusion:Our study, in accordance with the literature, revealed a great interindividual heterogeneity of the clinical phenotype of FVII deficiency. In addition, bleeding severity did not necessarily correlate with FVII:C and varies markedly between individuals with a similar FVII:C. This would explain the delay and the underestimation of the diagnosis. In addition, the family screening had a prominent effect in improving the earliness of the diagnosis and in ensuring an adequate monitoring of these Tunisian patients.

A novel mutation in the AGXT gene causing primary hyperoxaluria type I: genotype-phenotype correlation.

Primary hyperoxaluria type I (PH1) is an autosomal recessive metabolic disorder caused by inherited mutations in the AGXT gene encoding liver peroxisomal alanine : glyoxylate aminotransferase (AGT) which is deficient or mistargeted to mitochondria. PH1 shows considerable phenotypic and genotypic heterogeneity. The incidence and severity of PH1 varies in different geographic regions. DNA samples of the affected members from two unrelated Tunisian families were tested by amplifying and sequencing each of the AGXT exons and intron-exon junctions. We identified a novel frameshift mutation in the AGXT gene, the c.406_410dupACTGC resulting in a truncated protein (p.Gln137Hisfs*19). It is found in homozygous state in two nonconsanguineous unrelated families from Tunisia. These molecular findings provide genotype/phenotype correlations in the intrafamilial phenotypic and permit accurate carrier detection, and prenatal diagnosis. The novel p.Gln137Hisfs*19 mutation detected in our study extend the spectrum of known AGXT gene mutations in Tunisia.

Familial hematological malignancies: ASXL1 gene investigation.

Familial aggregation among patients with several hematological malignancies has been revealed. This emphasizes the importance of genetic factors. Only few genes predisposing to familial hematological malignancies have been reported until now due to the low occurrence. We have described in previous study PRF1 and CEBPA variants that might contribute to the background of genetic factors, which encourage us to extend our investigations to other cooperating genes. The aim of this study is to determine whether germline additional sex combs-like 1 (ASXL1) gene mutations may be involved? In this study, we investigated the candidate gene ASXL1 by direct sequencing in 88 unrelated Tunisian and French families with aggregated hematological malignancies. We report a new p.Arg402Gln germline missense substitution in two related Tunisian patients which has not been previously described. We identified here this variant for the first time in non-Hodgkin lymphoma. The p.Arg402Gln variant was not found in 200 control chromosomes. In silico analysis has predicted potential deleterious effect on ASXL1 protein. From an extended candidate genes analyzed in the field of familial hematological malignancies, ASXL1 might be involved. This variant should be considered since a potential damaging effect was predicted by in silico analysis, with a view to develop functional assay in order to investigate the biological assessment.

Deep Dermatophytosis and Inherited CARD9 Deficiency

BackgroundDeep dermatophytosis is a severe and sometimes life-threatening fungal infection caused by dermatophytes. It is characterized by extensive dermal and subcutaneous tissue invasion and by frequent dissemination to the lymph nodes and, occasionally, the central nervous system. The condition is different from common superficial dermatophyte infection and has been reported in patients with no known immunodeficiency. Patients are mostly from North African, consanguineous, multiplex families, which strongly suggests a mendelian genetic cause.MethodsWe studied the clinical features of deep dermatophytosis in 17 patients with no known immunodeficiency from eight unrelated Tunisian, Algerian, and Moroccan families. Because CARD9 (caspase recruitment domain–containing protein 9) deficiency has been reported in an Iranian family with invasive fungal infections, we also sequenced CARD9 in the patients.ResultsFour patients died, at 28, 29, 37, and 39 years of age, with clinically active deep dermatophytosis. No other severe infections, fungal or otherwise, were reported in the surviving patients, who ranged in age from 37 to 75 years. The 15 Algerian and Tunisian patients, from seven unrelated families, had a homozygous Q289X CARD9 allele, due to a founder effect. The 2 Moroccan siblings were homozygous for the R101C CARD9 allele. Both alleles are rare deleterious variants. The familial segregation of these alleles was consistent with autosomal recessive inheritance and complete clinical penetrance.ConclusionsAll the patients with deep dermatophytosis had autosomal recessive CARD9 deficiency. Deep dermatophytosis appears to be an important clinical manifestation of CARD9 deficiency. (Funded by Agence Nationale pour la Recherche and others.)

Clinical features and molecular genetics of two Tunisian families with abetalipoproteinemia

Abetalipoproteinemia (ABL) is a rare monogenic disease characterized by very low plasma levels of cholesterol and triglyceride and almost complete absence of apolipoprotein B (apoB)-containing lipoproteins. Typically, patients present with failure to thrive, acanthocytosis, pigmented retinopathy and neurological features. It has been shown that ABL results from mutations in the gene encoding the microsomal triglyceride transfer protein (MTTP). Sanger sequencing of MTTP was performed for two unrelated consanguineous Tunisian families with two affected individuals each, presenting a more severe ABL phenotype than previously reported in the literature. The patients were found to be homozygous for two novel mutations. In the first family, a nonsense mutation, c.2313T>A, leading to a truncated protein (p.Y771X) was identified. In the second family, a splice mutation, IVS 9+2T>G, was found. These mutations are believed to abolish the assembly and secretion of apoB-containing lipoproteins.

Chromosomal instability associated with a novel BLM frameshift mutation (c.1980‐1982delAA) in two unrelated Tunisian families with Bloom syndrome

The Bloom syndrome (BS) is an autosomal recessive disorder associated with dwarfism, immunodeficiency, reduced fertility and cancer risk. BS cells show genomic instability, particularly an hyper exchange between the sister chromatids due to a defective processing of the DNA replication intermediates. It is caused by mutations in the BLM gene which encodes a member of the RecQ family of DExH box DNA helicases. In this study, we reported cytogenetic, BLM linkage and mutational analyses for two affected Tunisian families. The Cytogenetic parameters were performed by chromosomal aberration (CA) and sister chromatid exchange (SCE) assays and results showed a significant increase in mean frequency of CA and SCE in BS cells. BLM linkage performed by microsatellite genotyping revealed homozygous haplotypes for the BS patients, evidence of linkage to BLM gene. Mutational analysis by direct DNA sequencing revealed a novel frameshift mutation (c.1980-1982delAA) in exon 8 of BLM gene, resulting in a truncated protein (p.Lys662fsX5). The truncated protein could explain genomic instability and its related symptoms in the BS patients. The screening of this mutation is useful for BS diagnosis confirmation in Tunisian families.

A double mutation in AGXT gene in families with primary hyperoxaluria type 1

Primary hyperoxaluria type 1 (PH1) is a severe autosomal recessive inherited disorder of glyoxylate metabolism caused by mutations in the AGXT gene on chromosome 2q37.3 that encodes the hepatic peroxisomal enzyme alanine:glyoxylate aminotransferase. These mutations are found throughout the entire gene and cause a wide spectrum of clinical severity. Rare in Europe, PH1 is responsible for 13% of the end stage renal failure in the Tunisian child. In the present work, we identified the double mutation c.32C>T (Pro11Leu) and c.731T>C (p.Ile244Thr) in AGXT gene in five unrelated Tunisian families with PH1 disease. Our results provide evidence regarding the potential involvement of c.32C>T, originally described as common polymorphism, on the resulting phenotype. We also reported an extreme intrafamilial heterogeneity in clinical presentation of PH1. Despite the same genetic background, the outcome of the affected members differs widely. The significant phenotypic heterogeneity observed within a same family, with a same genotype, suggests the existence of relevant modifier factors.

3-Phosphoglycerate Dehydrogenase Deficiency: Description of Two New Cases in Tunisia and Review of the Literature

3-Phosphoglycerate dehydrogenase (3-PGDH) deficiency is a rare autosomal recessive disorder of serine biosynthesis. It is typically characterized by congenital microcephaly, intractable seizures of infantile onset, and severe psychomotor retardation. Diagnosis is suspected on decreased l-serine levels in plasma and cerebrospinal fluid (CSF) and confirmed by genetic study. Early diagnosis in index cases allows supplementation in serine and prevention of fixed lesions. Prenatal diagnosis and genetic counseling allows prevention of secondary cases. We report on the two first unrelated Tunisian families with 3-PGDH deficiency confirmed by biochemical and genetic study. We discuss clinical, biochemical, imaging, electroencephalographic, and therapeutic aspects and review the literature.

Clinical and Molecular Findings of Ataxia With Oculomotor Apraxia Type 2 (AOA2) in 5 Tunisian Families

Ataxia with oculomotor apraxia type 2 (AOA2) is a recently described autosomal recessive cerebellar ataxia caused by mutations in the SETX gene. It is a rare monogenic disease characterized by progressive cerebellar ataxia, oculomotor apraxia, axonal sensorimotor neuropathy, and an elevated serum α-fetoprotein level. To date, >100 AOA2 patients have been described and 75 different mutations in the SETX gene have been identified. We report here the clinical and genetic findings of 13 AOA2 patients from 5 unrelated Tunisian consanguineous families. DNA was collected from probands and available family members, and the 24 SETX exons were screened by direct sequencing. Four different homozygous SETX gene mutations were identified. The missense mutation 915G>T [W305C] has been described previously in Algeria. The 3 other SETX mutations are novel, including a missense mutation c.7231C>T [R 2380 W], a nonsense mutation c.6475 C>T [R2098X], and a deletion c.7180-7183delAAAA [D2332fsX2343]. More extensive screening by molecular genetic analysis of SETX in patients with Friedreich ataxia-like phenotype may show that AOA2 is more common in Tunisia than previously thought.

Identification of a novel missense mutation in the ALDH7A1 gene in two unrelated Tunisian families with pyridoxine-dependent epilepsy

Pyridoxine-dependent Epilepsy (PDE) is a rare autosomal recessive disorder causing intractable seizures in neonates and infants. It is characterized by seizures that are resistant to common anticonvulsants, but patients respond well to the administration of pyridoxine. PDE is caused by ALDH7A1 genetic defect. Here, we report the disease-causative variant in the ALDH7A1 gene in two affected Tunisian families. Direct sequencing analysis revealed a novel missense mutation c.1364T>C (p.Leu455Pro). Using bioinformatic tools we suggested that this variant may have deleterious effects on ALDH7A1 protein structure and function.

High prevalence of the c.1227_1228dup (p.Glu410GlyfsX43) mutation in Tunisian families affected with MUTYH-associated-polyposis

Germline mutations in the base excision repair gene MUTYH have been associated with recessive inheritance of multiple colorectal adenomas. Screening of the MUTYH gene was carried on index cases of 10 unrelated Tunisian families and on available DNA samples from some members. Three germline mutations: c.536A>G (p.Y179C), c.1187 G>A (p.G396D) and c.1227_1228dup (p.Glu410GlyfsX43), were identified in the homozygous or compound heterozygous state in 8 out of 10 families. The c.1227_1228dup (p.Glu410GlyfsX43) mutation was the most frequent, since it was found in biallelic homozygous in 7 probands and 2 members of family F1 and in compound heterozygous associated with the c.536 A>G (p.Y179C) or c.1187 G>A (p.G396D) in family F2. Haplotype analysis revealed that the 8 families are unrelated. Moreover, in sporadic colorectal cancer, the c.1227_1228dup (p.Glu410GlyfsX43) mutation was identified in 13% of patients compared to the p.G396D and p.Y179C found in 1.2 and 2.12% respectively. Our data shows the high prevalence of the p.Glu410GlyfsX43 mutation in Tunisian families affected with MUTYH associated polyposis as well as in sporadic colorectal carcinoma.

Investigation of Four Genes Responsible for Autosomal Recessive Congenital Cataract and Highly Expressed in the Brain in Four Unrelated Tunisian Families

Purpose: To identify the causative gene for phenotypes associating autosomal recessive congenital cataract, mental retardation and congenital cataract, mental retardation and microcephaly in four unrelated Tunisian families. Methods: Four genes (EPHA2, GALK1, GCNT2, and CRYBB1) were selected based on expression in human brain and their known or putative function. Linkage analyses were performed for the four genes in multiple affected and unaffected families’ members and results were explored by the GeneMapper ID v3.2 software. Results: No linkage was identified for the four studied genes in the four families. Affected members of each family did not share common haplotypes in corresponding candidate regions containing selected gene. Conclusion: Although the four studied genes were reported responsible for autosomal recessive congenital cataract and highly expressed in the human brain, we report no linkage for EPHA2, GALK1, GCNT2, and CRYBB1 genes in four families with congenital cataract, mental retardation and congenital cataract, mental retardation and microcephaly.

DFNB66 and DFNB67 loci are non allelic and rarely contribute to autosomal recessive nonsyndromic hearing loss

We previously mapped the DFNB66 locus to an interval overlapping the DFNB67 region. Mutations in the LHFPL5 gene were identified as a cause of DFNB67 hearing loss (HL). However, screening of the coding exons of LHFPL5 did not reveal any mutation in the DFNB66 family. The objective of this study was to check whether DFNB66 and DFNB67 are distinctive loci and determining their contribution to HL. In the DFNB66 family, sequencing showed absence of mutations in the untranslated regions and the predicted promoter sequence of LHFPL5. Analysis of five microsatellites in the 6p21.31–22.3 region and screening of the LHFPL5 gene by DNA heteroduplex analysis in DHPLC revealed a novel mutation (c.89dup) in one out of 129 unrelated Tunisian families with autosomal recessive nonsyndromic (ARNS) HL. Our findings suggest that two distinct genes are responsible for DFNB66 and DFNB67 HL. These loci are likely to be a rare cause of ARNSHL.

Molecular analysis of mucopolysaccharidosis type I in Tunisia: identification of novel mutation and eight Novel polymorphisms.

Mucopolysaccharidosis type I (MPS I) is an autosomal recessive lysosomal storage disorder caused by a genetic defect in alpha-L-iduronidase (IDUA) which is involved in the degradation of dermatan and heparan sulfates. The disease has severe and milder phenotypic subtypes. The aim of this study was the detection of mutations in the IDUA gene from 12 additional MPS I patients with various clinical phenotypes (severe, 8 cases; intermediate, 3 cases; mild, 1 case).Patients and methodsIn this study, the IDUA mutations in eight unrelated Tunisian families were performed by amplifying and sequencing the IDUA exons and intron-exon jonctions.ResultsFive IDUA mutations were detected: one is the L578Q, a novel mutation found, in milder patient. The others were the previously described: P533R, Y581X, F602X and R628X that produce a severe and intermediate phenotype. In addition, eighteen variants, including eight previously unreported polymorphisms (IVS6+21c > a, IVS7+79c > t, IVS7-45 g > c, IVS9+36t > c, IVS10+140c > a, IVS11+33c > t, IVS12+13c > t and IVS12-31c > g), were detected.ConclusionThis paper, showed a heterogeneous pattern of mutations and polymorphisms among Tunisian patients.

Whole mitochondrial genome screening in two families with hearing loss: detection of a novel mutation in the 12S rRNA gene

Sensorineural hearing loss has been described in association with different mitochondrial multisystemic syndromes, often characterized by an important neuromuscular involvement. Until now, mutations in mitochondrial DNA, especially in the 12S rRNA, the tRNASer(UCN) and the tRNALeu(UUR) genes, were implicated in syndromic or non-syndromic hearing loss either as a primary cause or as predisposing factors. In the present study, we performed a whole mitochondrial genome screening in two unrelated Tunisian families with inherited hearing loss. Results showed the presence of a novel mutation in the mitochondrial 12S rRNA gene in the two probands of these two families who belong to two different haplogroups: L3 and H6a1. The m.735A>G mutation affects a conserved nucleotide of the mitochondrial 12S rRNA gene in primates and other species and had a conservation index of 78.5% (11/14). We also detected known polymorphisms and sic novel mitochondrial variants. The present study confirmed that the mitochondrial 12S rRNA gene is a hot spot for mutations associated with hearing impairment.