Genetic linkage analysis of DFNB39 locus in families with autosomal recessive non-syndromic hearing loss (ARNSHL) from Khuzestan province

Background and aims: Hearing loss (HL) is a most common sensory deficit in humans and approximately one in 1,000 newborns has severe-to-profound HL. About 50% of HL cases are inherited and approximately 70 percent of HL cases are Non-syndromic that about 80 percent of this type of HL is inherited in recessive manner (ARNSHL). This is a heterogeneous disease and its prevalence is higher in developing countries. In Iran due to high rate of consanguinity has high frequency, too. The purpose of the present study was to investigate genetic linkage analysis of DFNB39 locus in families with autosomal recessive nonsyndromic HL from Khuzestan province. Methods: In this descriptive laboratory study, to determine type and frequency of HGF mutations 300 individuals of 25 families from Khuzestan province with autosomal recessive nonsyndromic hearing loss were examined. Selected families in this study had consanguinity and had at least 2 patients and also they were negative for GJB2 gene mutations. Linkage analysis was performed by 6 markers STR (Short tandem repeats) which were located in or were tightly linked to DFNB39 locus conventional PCR and PAGE. Results: After examining different families, it was revealed non of the families did not show linkage to the DFNB39 locus. Lack of HGF gene mutations in mentioned family suggests that the HGF's mutations probably have no role in causing HL in the studied families. Conclusion: Based on the results of this study, DFNB39 locus may not be important role in causing hearing loss of population studied. However, further studies are necessary to determine more precisely the role of this locus in hearing loss in Iranian population

Genetic linkage analysis of the DFNB48 and DFNB98 loci in families with Autosomal Recessive Non-Syndromic Hearing Loss (ARNSHL) from Khouzestan province

Background and aims: Hearing loss, a sensorineural disorder, is one of the most common congenital impairments, occurring in approximately 1 in 500 newborns. Hearing loss is a highly heterogenic disease and half of the cases of deafness are attributed to genetic causes; environmental and unknown factors account for the remainder. Non-syndromic type forms 70% of hearing loss cases. Pattern of inheritance of nearly 80% of this type of HL is recessive autosomal. Iranian population provides a valuable genetic resource to study this kind of HL because of high ratio of consanguinity. In this study, genetic linkage of DFNB48 (CIB2) and DFNB98 (TSPEAR) is investigated in families with ARNSHL impairment from Khouzestan province. Methods: In this descriptive study 300 individuals of 25 families with hearing loss were examined in order to determine type and frequency of mutation of DFNB48 and DFNB98 loci in Khouzestan province. Families' selection had some criteria. Families with healthy parents, consanguineous marriage and negative result for mutations of GJB2 gene with at least two affected individuals were selected. 3 families which were detected positive for mutations of GJB2 gene were excluded from study. Linkage analysis was done for 22 families by using six STR markers which were located in or were tightly linked to each locus. Results: None of these families inspected by linkage analysis was linked to the DFNB48 or DFNB98 loci. Conclusion: Considering these results it seems that CIB2 and TSPEAR genes mutations have not important roles in hearing loss in Khouzestan province

Unexpected identification of a recurrent mutation in the DLX3 gene causing amelogenesis imperfecta

Objective To identify the molecular genetic aetiology of a family with autosomal dominant amelogenesis imperfecta (AI). Subjects and Methods DNA samples were collected from a six-generation family, and the candidate gene approach was used to screen for the enamelin (ENAM) gene. Whole-exome sequencing and linkage analysis with SNP array data identified linked regions, and candidate gene screening was performed. Results Mutational analysis revealed a mutation (c.561_562delCT and p.Tyr188Glnfs*13) in the DLX3 gene. After finding a recurrent DLX3 mutation, the clinical phenotype of the family members was re-examined. The proband's mother had pulp elongation in the third molars. The proband had not hair phenotype, but her cousin had curly hair at birth. Conclusions In this study, we identified a recurrent 2-bp deletional DLX3 mutation in a new family. The clinical phenotype was the mildest one associated with the DLX3 mutations. These results will advance the understanding of the functional role of DLX3 in developmental processes.OAIID:RECH_ACHV_DSTSH_NO:T201604269RECH_ACHV_FG:RR00200001ADJUST_YN:EMP_ID:A080446CITE_RATE:2FILENAME:Kim_et_al-2016-Oral_Diseases.pdfDEPT_NM:치의학과EMAIL:[email protected]_YN:YFILEURL:https://srnd.snu.ac.kr/eXrepEIR/fws/file/1f942450-fa58-4bd3-8e50-692d90fed3c6/linkCONFIRM:

Heterozygous missense variants of LMX1A lead to nonsyndromic hearing impairment and vestibular dysfunction

Unraveling the causes and pathomechanisms of progressive disorders is essential for the development of therapeutic strategies. Here, we identified heterozygous pathogenic missense variants of LMX1A in two families of Dutch origin with progressive nonsyndromic hearing impairment (HI), using whole exome sequencing. One variant, c.721G > C (p.Val241Leu), occurred de novo and is predicted to affect the homeodomain of LMX1A, which is essential for DNA binding. The second variant, c.290G > C (p.Cys97Ser), predicted to affect a zinc-binding residue of the second LIM domain that is involved in protein–protein interactions. Bi-allelic deleterious variants of Lmx1a are associated with a complex phenotype in mice, including deafness and vestibular defects, due to arrest of inner ear development. Although Lmx1a mouse mutants demonstrate neurological, skeletal, pigmentation and reproductive system abnormalities, no syndromic features were present in the participating subjects of either family. LMX1A has previously been suggested as a candidate gene for intellectual disability, but our data do not support this, as affected subjects displayed normal cognition. Large variability was observed in the age of onset (a)symmetry, severity and progression rate of HI. About half of the affected individuals displayed vestibular dysfunction and experienced symptoms thereof. The late-onset progressive phenotype and the absence of cochleovestibular malformations on computed tomography scans indicate that heterozygous defects of LMX1A do not result in severe developmental abnormalities in humans. We propose that a single LMX1A wild-type copy is sufficient for normal development but insufficient for maintenance of cochleovestibular function. Alternatively, minor cochleovestibular developmental abnormalities could eventually lead to the progressive phenotype seen in the families

Heterozygous missense variants of LMX1A lead to nonsyndromic hearing impairment and vestibular dysfunction

Neuro Imaging Researc

Mapping Chromosomal Loci in Specific Language Impairment: A Pedigree-Focused Approach

Specific language impairment (SLI) is characterized by a delay in the mastery of language despite average or above average nonverbal intelligence (IQ). There are multiple assessments used in practice to measure the language abilities of individuals with SLI. Standardized language assessments in conjunction with a measure of nonverbal IQ are the most crucial for distinguishing individuals with and without SLI in research practice. Studies have found that the incidence of SLI in extended relatives of probands is significantly higher than population matched relatives of controls. The heritability estimates of SLI are higher in MZ twins than DZ twins. Both family and twin studies indicate genetic involvement in the transmission of SLI. Previous genetic studies in SLI have found candidate chromosomal loci on 2q24, 6p21, 10q26, 12p13, 21q, and several candidate genes including TM4SF20, NFXL1, CNTNAP2, KIAA0319, CMIP, and ATP2C2 have been implicated in SLI. However, the causes of SLI are not well understood and investigation may benefit from family-based approaches. The current study approached genetic investigation of SLI one pedigree at a time. We report SLI loci on chromosomes 4q, 3p, 6q, 9q, 10q, 12p, 14q and 15q linked with the omnibus standard score categorical phenotype, indicating genetic and phenotypic heterogeneity of SLI. These findings support the discussion of previous hypotheses that SLI is a polygenic disorder, with multiple loci reported in a few of the families included in this report