A novel locus for autosomal dominant non-syndromic deafness, DFNA53, maps to chromosome 14q11.2-q12

Background

Non‐syndromic hearing loss is among the most genetically heterogeneous traits known in humans. To date, at least 50 loci for autosomal dominant non‐syndromic sensorineural hearing loss (ADNSSHL) have been identified by linkage analysis.

Objective

To report the mapping of a novel autosomal dominant deafness locus on the long arm of chromosome 14 at 14q11.2‐q12, DFNA53, in a large multigenerational Chinese family with post‐lingual, high frequency hearing loss that progresses to involve all frequencies.

Results

A maximum multipoint LOD score of 5.4 was obtained for marker D14S1280. The analysis of recombinant haplotypes mapped DFNA53 to a 9.6 cM region interval between markers D14S581 and D14S1021. Four deafness loci (DFNA9, DFNA23, DFNB5, and DFNB35) have previously been mapped to the long arm of chromosome 14. The critical region for DFNA53 contains the gene for DFNA9 but does not overlap with the regions for DFNB5, DFNA23, or DFNB35. Screening of the COCH gene (DFNA9), BOCT, EFS, and HSPC156 within the DFNA53 interval did not identify the cause for deafness in this family.

Conclusions

Identifying the DFNA53 locus is the first step in isolating the gene responsible for hearing loss in this large multigeneration Chinese family.     

A novel locus for autosomal dominant, non-syndromic hearing impairment (DFNA18) maps to chromosome 3q22 immediately adjacent to the DM2 locus

Investigating a large German pedigree with non-syndromic hearing impairment of early onset and autosomal dominant mode of inheritance, linkage to known DFNA loci was excluded and in a subsequent genomic scan the phenotype was mapped to a 10-cM interval on chromosome 3q22; a maximum two-point lod score of 3.77 was obtained for the marker D3S1292. The new locus, DFNA18, is excluded from neighbouring deafness loci, DFNB15 and USH3, and it overlaps with the recently described DM2/PROMM locus. As hearing loss has been described as one feature of the PROMM phenotype, the DFNA18 gene might also be responsible for hearing loss in DM2/PROMM.     

A novel locus for autosomal dominant congenital cerulean cataract maps to chromosome 12q

Cataracts are the commonest cause of blindness worldwide. Inherited cataract is a clinically and genetically heterogeneous disease that most often shows autosomal dominant inheritance. In this study, we report the identification of a novel locus for cerulean cataract type 5 (CCA5), also known as blue-dot cataract on chromosome 12q24. To date, four loci for autosomal dominant congenital cerulean cataract have been mapped on chromosomes, 17q24, 22q11.2–12.2, 2q33–35 and 16q23.1. To map this locus we performed genetic linkage analysis using microsatellite markers in a five-generation English family. After the exclusion of all known loci and several candidate genes we obtained significantly positive LOD score (Z) for marker D12S1611 (Z_max=3.60; at θ=0). Haplotype data indicated that CCA5 locus lies within a region of 14.3 Mb interval between the markers D12S1718 and D12S1723. Our data are strongly suggestive of a new locus for CCA5 on chromosome 12.     

A novel locus for autosomal dominant non-syndromic hearing loss, DFNA31, maps to chromosome 6p21.3

Objective:To investigate the genes involved in a Dutch family with NSSHL.

Methods:Linkage analysis in a large Dutch pedigree with progressive bilateral loss of the mid and high frequencies, in which a novel dominant locus for postlingual NSSHL (DFNA31) has been identified.

Results:DFNA31 was found to be located in a 7.5 cM region of chromosome 6p21.3 between D6S276 (telomeric) and D6S273 (centromeric), with a maximum two point LOD score of 5.99 for D6S1624. DNA sequencing of coding regions and exon/intron boundaries of two candidate genes (POU5F1, GABBR1) in this interval did not reveal disease causing mutations.

Conclusions:Haplotype analysis indicated that the genetic defect in this family does not overlap the DFNA13 and DFNA21 regions that are also located on 6p. Identification of the disease gene will be of major importance in understanding the pathophysiology of hearing impairment.

     

A novel locus for autosomal dominant cone-rod dystrophy maps to chromosome 10q

Here we report recruitment of a three-generation Romani (Gypsy) family with autosomal dominant cone-rod dystrophy (adCORD). Involvement of known adCORD genes was excluded by microsatellite (STR) genotyping and linkage analysis. Subsequently, two independent total-genome scans using STR markers and single-nucleotide polymorphisms (SNPs) were performed. Haplotype analysis revealed a single 6.7-Mb novel locus between markers D10S1757 and D10S1782 linked to the disease phenotype on chromosome 10q26. Linkage analysis gave a maximum LOD score of 3.31 for five fully informative STR markers within the linked interval corresponding to the expected maximum in the family. Multipoint linkage analysis of SNP genotypes yielded a maximum parametric linkage score of 2.71 with markers located in the same chromosomal interval. There is no previously mapped CORD locus in this interval, and therefore the data reported here is novel and likely to identify a new gene that may eventually contribute to new knowledge on the pathogenesis of this condition. Sequencing of several candidate genes within the mapped interval led to negative findings in terms of the underlying molecular pathogenesis of the disease in the family. Analysis by comparative genomic hybridization excluded large chromosomal aberrations as causative of adCORD in the pedigree.     

Mapping of a new autosomal dominant non-syndromic hearing loss locus (DFNA43) to chromosome 2p12

Hearing impairment (HI) is the most frequent sensory defect with wide genetic heterogeneity. Approximately 80% of genetic hearing loss is non-syndromic and 15-25% of exhibit autosomal dominant inheritance. We analysed an Italian three generation family in which non-syndromic hearing impairment is transmitted as an autosomal dominant trait. Onset of HI in all affected subjects occurred in the second decade of life, with subsequent gradual progression from moderate to profound loss. HI was bilateral and symmetrical, involving all frequencies. After exclusion of the known DFNA loci with markers from the Hereditary Hearing Loss Homepage (URL: http://dnalab-www.uia.ac.be/dnalab/hhh), a genome wide scan was carried out using 358 highly informative microsatellite markers. Significant linkage (Zmax=4.21, theta=0) was obtained with chromosome 2p12 markers. The results were confirmed by multipoint analysis (Zmax=4.51), using the location score method. Haplotype analysis defined a 9.6 cM disease gene interval on chromosome 2 without overlap with the other identified loci. Fine mapping and identification of candidate genes are in progress.     

A locus for autosomal dominant progressive non-syndromic hearing loss, DFNA27, is on chromosome 4q12-13.1

We ascertained a large North American family, LMG2, segregating progressive, non-syndromic, sensorineural hearing loss. A genome-wide scan identified significant evidence for linkage (maximum logarithm of the odds (LOD) score = 4.67 at θ  = 0 for D4S398) to markers in a 5.7-cM interval on chromosome 4q12-13.1. The DFNA27 interval spans 8.85 Mb and includes at least 61 predicted and 8 known genes. We sequenced eight genes and excluded them as candidates for the DFNA27 gene.     

A novel locus for non-syndromic sensorineural deafness (DFN6) maps to chromosome Xp22

Non-syndromic X-linked deafness is highly heterogeneous. At least five different clinical forms have been described, but only two loci have been mapped. Here we report a Spanish family affected by a previously undescribed X-linked form of hearing impairment. Deafness is non- syndromic, sensorineural, and progressive. In affected males, the auditory impairment is first detected at school age, affecting mainly the high frequencies. Later it evolves to become severe to profound, involving all frequencies for adulthood. Carrier females manifest a moderate hearing impairment in the high frequencies, with the onset delayed to the fourth decade of life. Deafness was assumed to be X- linked dominant, with incomplete penetrance and variable expressivity in carrier females. The family was genotyped for a set of microsatellite markers evenly spaced at intervals of about 10 cM. We found evidence of linkage to markers in the Xp22 region (maximum lod score of 5.30 at theta = 0.000 for DXS8036 and for DXS8022). The position of the novel deafness locus (DFN6) was refined by haplotype analysis. Mapping of the breakpoints in two critical recombinants allowed us to define an interval for DFN6, delimited by DXS7108 on the distal side and by DXS7105 on the proximal side, and spanning a genetic distance of about 15 cM.      

A gene for autosomal dominant late-onset progressive non-syndromic hearing loss, DFNA10, maps to chromosome 6

Late-onset non-syndromic hearing impairment is the most common type of neurological dysfunction in the elderly. It can be either acquired or inherited, although the relative impact of heredity on this type of loss is not known. To date, nine different genes have been localized, but none has been cloned. Using an extended American family in which a gene for autosomal dominant late-onset non-syndromic hearing impairment is segregating, we have identified a new locus, DFNA10, on chromosome 6.      

A gene for non-syndromic autosomal dominant progressive postlingual sensorineural hearing loss maps to chromosome 14q12-13

We report a novel locus responsible for postlingual progressive sensorineural hearing loss (designated DFNA9) that maps to chromosome 14q12-13. A large kindred with autosomal dominant transmission of non- syndromic hearing loss was clinically studied. Hearing in affected individuals deteriorated at approximately 20 years of age and progressed to anacusis in the fifth decade. A random genome-wide search using polymorphic short tandem repeats demonstrated linkage with D14S121 (maximum two point LOD score = 6.19, theta = 0). Haplotype analysis of recombination events defined a 9 cM disease interval, between D14S252 and D14S49.      

A novel autosomal recessive non-syndromic deafness locus (DFNB35) maps to 14q24.1-14q24.3 in large consanguineous kindred from Pakistan

Autosomal recessive nonsyndromic deafness is one of the most frequent forms of inherited hearing impairment. Over 30 autosomal recessive nonsyndromic hearing loss loci have been mapped, and 15 genes have been isolated. Of the over 30 reported autosomal recessive nonsyndromic hearing loss (NSHL) loci, the typical phenotype is prelingual non-progressive severe to profound hearing loss with the exception of DFNB8, which displays postlingual onset and DFNB13, which is progressive. In this report we describe a large inbred kindred from a remote area of Pakistan, comprising six generations and segregating autosomal recessive nonsyndromic prelingual deafness. DNA samples from 24 individuals were used for genome wide screen and fine mapping. Linkage analysis indicates that in this family the NSHL locus, (DFNB35) maps to a 17.54 cM region on chromosome 14 flanked by markers D14S57 and D14S59. Examination of haplotypes reveals a region that is homozygous for 11.75 cM spanning between markers D14S588 and D14S59. A maximum two-point LOD score of 5.3 and multipoint LOD score of 7.6 was obtained at marker D14S53. The interval for DFNB35 does not overlap with the regions for DFNA9, DFNA23 or DFNB5.     

DFNB20: a novel locus for autosomal recessive, non-syndromal sensorineural hearing loss maps to chromosome 11q25-qter

Autosomal recessive non-syndromal deafness is an extremely heterogeneous condition with at least 19 loci (DFNB1-19) already described. We have used autozygosity mapping to localise a further novel locus, DFNB20, to chromosome 11q25-qter in a consanguineous family originating from Pakistan. A region of homozygosity was observed in affected individuals spanning the interval D11S969-qter.     

A new locus (DFNA47) for autosomal dominant non-syndromic inherited hearing loss maps to 9p21-22 in a large Italian family

Hearing loss is the most common sensory disorder in humans, and genetic factors are a major cause. Approximately 15-20% of genetic cases exhibit an autosomal dominant pattern of transmission. So far, 41 autosomal dominant loci have been mapped and 17 genes have been identified. Here we report the mapping of a novel locus for autosomal dominant non-syndromic hearing loss, DFNA47, to chromosome 9p21-22 in a large multigenerational Italian family with progressive hearing impairment. Most affected individuals noticed hearing impairment after their teens with subsequent gradual progression to a moderate-severe loss. There were no obvious vestibular dysfunction and other associated abnormalities. A maximum lod score of 3.14 was obtained with marker D9S157 (at theta=0) after a genome wide search. The study of additional markers allowed us to confirm this region with positive lod scores of 3.58 (at theta=0 from D9S285) and of 3.67 (at theta=0 from D9S162). Recombinants define a region of approximately 9 cM flanked by markers D9S268 and D9S942. Multipoint linkage analysis showed a Lod score of 4.26. Few known genes map to the region, and those possibly related by function to hearing are being screened for disease-causing mutations.     

A gene for autosomal dominant hearing impairment (DFNA14) maps to a region on chromosome 4p16.3 that does not overlap the DFNA6 locus

Non-syndromic hearing impairment is one of the most heterogeneous hereditary conditions, with more than 40 reported gene localisations. We have identified a large Dutch family with autosomal dominant non-syndromic sensorineural hearing impairment. In most patients, the onset of hearing impairment is in the first or second decade of life, with a slow decline in the following decades, which stops short of profound deafness. The hearing loss is bilateral, symmetrical, and only affects low and mid frequencies up to 2000 Hz. In view of the phenotypic similarities of this family with an American family that has been linked to chromosome 4p16.3 (DFNA6), we investigated linkage to the DFNA6 region. Lod score calculations confirmed linkage to this region with two point lod scores above 6. However, as haplotype analysis indicated that the genetic defect in this family is located in a 5.6 cM candidate region that does not overlap the DFNA6 region, the new locus has been named DFNA14.     

Mapping of a new autosomal dominant nonsyndromic hearing loss locus (DFNA30) to chromosome 15q25-26

Hearing impairment is the most common inherited human sensory defect. Nonsyndromic Hearing Impairment (NSHI) is the most genetically heterogeneous trait known. Over 70 loci have been mapped and a total of 19 genes have been identified. We report here a novel locus (DFNA 30) for autosomal dominant NSHI that we mapped to chromosome 15q25-26 in an Italian four-generation family. The haplotype analysis has identified a critical interval of 18 cM between markers D15S151 and D15S130. This region does not overlap with DFNB16 locus but partially coincides with the otosclerosis (OTS) locus. Localisation of the locus DFNA30 is a first step towards the identification of the gene.     

Localization of a novel autosomal recessive non-syndromic hearing impairment locus DFNB55 to chromosome 4q12-q13.2

Hereditary hearing impairment (HI) is the most genetically heterogeneous trait known in humans. So far, 54 autosomal recessive non-syndromic hearing impairment (ARNSHI) loci have been mapped, and 21 ARNSHI genes have been identified. Here is reported the mapping of a novel ARNSHI locus, DFNB55, to chromosome 4q12-q13.2 in a consanguineous Pakistani family. A maximum multipoint LOD score of 3.5 was obtained at marker D4S2638. The region of homozygosity and the 3-unit support interval are flanked by markers D4S2978 and D4S2367. The region spans 8.2 cm on the Rutgers combined linkage-physical map and contains 11.5 Mb. DFNB55 represents the third ARNSHI locus mapped to chromosome 4.     

A fourth locus for autosomal dominant hypercholesterolemia maps at 16q22.1

Autosomal dominant hypercholesterolemia (ADH) is characterized by isolated increase in plasmatic low-density lipoprotein (LDL) cholesterol levels associated with high risk of premature cardiovascular disease. Mutations in LDLR, APOB, and PCSK9 genes have been shown to cause ADH. We now report further genetic heterogeneity of ADH through the study of a large French family in which the involvement of these three genes was excluded. A genome-wide scan mapped the disease-causing gene, named HCHOLA4, at 16q22.1 in a 7.89-Mb interval containing 154 genes with a maximum LOD score of 3.9. To reduce the linked region, we genotyped 18 smaller non-LDLR/non-APOB/non-PCSK9-ADH families at the HCHOLA4 locus. Six families did not exclude linkage to the locus, but none allowed reduction of the disease interval. The 154 regional genes were sorted according to the function of the encoded protein and tissue expression profiles, and 57 genes were analyzed through sequencing of their coding region and close flanking intronic parts. No disease-causing mutation was identified in these families, particularly in the LCAT gene. Finally, our results also show the existence of other ADH genes as nine families were neither linked to LDLR, APOB, and PCSK9 genes nor to the new HCHOLA4 locus.