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Mahdieh N.,Tarbiat Modares University | Rabbani B.,Tehran University of Medical Sciences | Wiley S.,University of Cincinnati | Akbari M.T.,Tarbiat Modares University | And 2 more authors.
Journal of Human Genetics

Hearing loss (HL) is the most prevalent sensory defect affecting 1 in 500 neonates. Genetic factors are involved in half of the cases. The extreme heterogeneity of HL makes it difficult to analyze and determine the accurate genetic causes of the impairment. Up to now, 10 genes, namely, GJB2, GJB6, SLC26A4, TECTA, PJVK, Col11A2, Myo15A, TMC1, RDX and microRNA (miR-183), have been studied in an Iranian population. The prevalence of HL in Iran was estimated to be 2-3 times higher than that in other parts of the world. Here, the most common bases of congenital nonsyndromic hearing loss (NSHL) are discussed. We reviewed GJB2, GJB6 (large deletion), TECTA, SLC26A4 and PEJVK mutations, and studied their frequencies and distributions in different ethnic groups in 1934, 500, 121, 80 and 34 unrelated families throughout Iran, respectively. GJB2 mutation was the most common factor causing NSHL, with a mean frequency of 18.17% in the Iranian population. The importance of Iran's geographical location in the migration pathway from west to east through the silk route was also highlighted. SLC26A4 and TECTA mutations were the second and third main reasons of HL and accounted for up to 10 and 4% of prelingual HL in Iran, respectively. Mutations in GJB2, SLC26, TECTA and PJVK genes have an important role in HL in Iran and a screening test should be generated for better intervention and diagnosis programs. © 2010 The Japan Society of Human Genetics All rights reserved. Source

Raeisi M.,Kawsars Human Genetic Research Center | Mahdieh N.,Ilam University | Yousefzadeh A.,Pars Hospital Laboratory | Vahidi R.,Kawsars Human Genetic Research Center | And 3 more authors.
Clinical Laboratory

Background: Neonatal screening for PKU is carried out nationally and our center is one of the referral centers for molecular analysis of PKU in Iran. Hyperphenylalaninemias are common disorders of phenyalanine catabolism. Six genes, including PAH, PTPS, DHPR, GTPCH, SR, and PCBD, independently play a role in this disorder. Methods: A 2-year-old boy was referred to our center for genetic diagnosis of PKU. PAH gene was sequenced but no mutation was found. Using the STR based linkage mapping approach, BH4-metabolizing genes were screened. Result: A pattern of autozygosity by descent (ABD) suggested that the PCBD gene may be involved in this family. The PCBD gene was sequenced and a homozygous T > C substitution (X105Q) was found in the termination codon. Conclusions: Although most of the reported mutations in PCBD gene are single substitutions or premature stop codons causing a benign or transient form of BH4 deficiency, this novel mutation was found in the stop codon. Source

Mahdieh N.,Tarbiat Modares University | Shirkavand A.,Kawsars Human Genetic Research Center | Shirkavand A.,Razi University | Raeisi M.,Kawsars Human Genetic Research Center | And 4 more authors.
Biochemical and Biophysical Research Communications

Mutations in the GJB2 gene are the most common cause of nonsyndromic autosomal recessive sensorineural hearing loss (HL). A few mutations in GJB2 have also been reported to cause dominant nonsyndromic HL. Here we report a large inbred family including two individuals with nonsyndromic sensorineural hearing loss. A dominant GJB2 mutation, c.551G>A (p.R184Q), was detected in the proband, yet his parents were negative for the mutation. The second affected person had heterozygous c.35delG mutation, which was inherited from his father. Large deletions of the GJB6 gene were not detected in this family. This study highlights the importance of mutation analysis in all affected cases within a pedigree. © 2010. Source

Mahdieh N.,Tarbiat Modares University | Bagherian H.,Kawsars Human Genetic Research Center | Shirkavand A.,Kawsars Human Genetic Research Center | Shirkavand A.,Razi University | And 3 more authors.
International Journal of Pediatric Otorhinolaryngology

Hearing loss is the most common sensory defect in the world. The genetic basis of this condition is very complex. Molecular variations in GJB2 gene are the common cause of hearing impairment in Caucasians. One expects that affected members of a family with same mutation have similar phenotype. Here, we report phenotypic variability in hearing loss among the members of a Lur family. Two brothers from a Lur family from Lurestan province in western Iran with variable degrees of nonsyndromic sensorineural hearing loss were evaluated for genetic counseling. Clinical examinations, audiological tests and molecular studies including GJB2 gene sequencing and detection of Δ(GJB6-D13S1830) deletion were performed. Sequencing analysis of GJB2 gene revealed delE120 mutation in both brothers in homozygous form. Since one of them was profoundly deaf and the other was mild hearing loss and had normal conversation, we were expecting different genotypes or other causative effects. Δ(GJB6-D13S1830) was not found. Phenotypic variability between members of different families with the same type of mutation can be expected which may be due to the role of different modifying factors, unrecognized gap junction isoforms, or polymorphism effects. © 2010 Elsevier Ireland Ltd. Source

Bademci G.,University of Miami | Foster J.,University of Miami | Mahdieh N.,Tehran University of Medical Sciences | Bonyadi M.,University of Tabriz | And 28 more authors.
Genetics in Medicine

Purpose:Autosomal recessive nonsyndromic deafness (ARNSD) is characterized by a high degree of genetic heterogeneity, with reported mutations in 58 different genes. This study was designed to detect deafness-causing variants in a multiethnic cohort with ARNSD by using whole-exome sequencing (WES).Methods:After excluding mutations in the most common gene, GJB2, we performed WES in 160 multiplex families with ARNSD from Turkey, Iran, Mexico, Ecuador, and Puerto Rico to screen for mutations in all known ARNSD genes.Results:We detected ARNSD-causing variants in 90 (56%) families, 54% of which had not been previously reported. Identified mutations were located in 31 known ARNSD genes. The most common genes with mutations were MYO15A (13%), MYO7A (11%), SLC26A4 (10%), TMPRSS3 (9%), TMC1 (8%), ILDR1 (6%), and CDH23 (4%). Nine mutations were detected in multiple families with shared haplotypes, suggesting founder effects.Conclusion:We report on a large multiethnic cohort with ARNSD in which comprehensive analysis of all known ARNSD genes identifies causative DNA variants in 56% of the families. In the remaining families, WES allows us to search for causative variants in novel genes, thus improving our ability to explain the underlying etiology in more families.Genet Med 18 4, 364-371. © American College of Medical Genetics and Genomics. Source

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