DFNB44, a novel autosomal recessive non-syndromic hearing impairment locus, maps to chromosome 7p14.1-q11.22

The genetic etiology for many forms of hearing impairment (HI) is very diverse. Non-syndromic HI (NSHI) is one of the most heterogeneous traits known. Autosomal recessive forms of prelingual HI account for approximately 75% of hereditary cases. A novel autosomal recessive NSHI locus, DFNB44, was mapped to a 20.9 cM genetic interval on chromosome 7p14.1-q11.22, according to the Marshfield genetic map, in a consanguineous Pakistani family. Multipoint linkage analysis resulted in a maximum LOD score of 5.0 at marker D7S1818. The 3-unit support interval ranged from marker D7S2209 to marker D7S2435, spanning a 30.1 Mb region on the sequence-based physical map.     

DFNB89, a novel autosomal recessive nonsyndromic hearing impairment locus on chromosome 16q21-q23.2

DFNB89 is a novel autosomal recessive nonsyndromic hearing impairment (ARNSHI) locus that was mapped to 16q21-q23.2. Linkage to the region was established by carrying out genome-wide linkage scans in two unrelated, consanguineous Pakistani families segregating ARNSHI. The maximum multipoint LOD score is 9.7 for both families and for each family, a significant maximum LOD score of 6.0 and 3.7 were obtained. The 3-unit support interval and the region of homozygosity for the two families extend from rs717293 (chr16: 62.1?Mb) to rs728929 (chr16: 78.2?Mb) and contain 16.1?Mb of sequence. A total of 146 genes are within the DFNB89 interval. Eight candidate genes, CALB2, CDH1, CDH3, CDH11, HAS3, NOB1, PLEKHG4 and SMPD3, were sequenced, but no potentially causal variants were discovered. DFNB89 is the second ARNSHI locus mapped to chromosome 16.     

A novel autosomal recessive non-syndromic hearing impairment locus (DFNB47) maps to chromosome 2p25.1-p24.3

Hereditary hearing impairment (HI) displays extensive genetic heterogeneity. Autosomal recessive (AR) forms of prelingual HI account for ~75% of cases with a genetic etiology. A novel AR non-syndromic HI locus (DFNB47) was mapped to chromosome 2p25.1-p24.3, in two distantly related Pakistani kindreds. Genome scan and fine mapping were carried out using microsatellite markers. Multipoint linkage analysis resulted in a maximum LOD score of 4.7 at markers D2S1400 and D2S262. The three-unit support interval was bounded by D2S330 and D2S131. The region of homozygosity was found within the three-unit support interval and flanked by markers D2S2952 and D2S131, which corresponds to 13.2 cM according to the Rutgers combined linkage-physical map. This region contains 5.3 Mb according to the sequence-based physical map. Three candidate genes, KCNF1, ID2 and ATP6V1C2 were sequenced, and were found to be negative for functional sequence variants.     

DFNB68, a novel autosomal recessive non-syndromic hearing impairment locus at chromosomal region 19p13.2

From a large collection of families with autosomal recessive non-syndromic hearing impairment (NSHI) from Pakistan, linkage has been established for two unrelated consanguineous families to 19p13.2. This new locus was assigned the name DFNB68. A 10 cM genome scan and additional fine mapping were carried out using microsatellite marker loci. Linkage was established for both families to DFNB68 with maximum multipoint LOD scores of 4.8 and 4.6. The overlap of the homozygous regions between the two families was bounded by D19S586 and D19S584, which limits the locus interval to 1.9 cM and contains 1.4 Mb. The genes CTL2, KEAP1 and CDKN2D were screened but were negative for functional sequence variants.Regie Lyn P. Santos and Muhammad Jawad Hassan contributed equally to this work.     

A novel autosomal recessive non-syndromic deafness locus, DFNB66, maps to chromosome 6p21.2-22.3 in a large Tunisian consanguineous family

Hereditary non-syndromic deafness is extremely heterogeneous. Autosomal recessive forms account for approximately 80% of genetic cases. Autosomal recessive non-syndromic sensorineural deafness segregating in a large consanguineous Tunisian family was mapped to chromosome 6p21.2-22.3. A maximum lod score of 5.36 at theta=0 was obtained for the polymorphic microsatellite marker IR2/IR4. Haplotype analysis defined a 16.5-Mb critical region between microsatellite markers D6S1602 and D6S1665. The screening of 3 candidate genes, COL11A2, BAK1 and TMHS, did not reveal any disease causing mutation, suggesting that this is a novel deafness locus, which has been named DFNB66. A search in the Human Cochlear EST Library for ESTs located in this critical interval allowed us to identify several candidates. Further investigations on these candidates are needed in order to identify the deafness-causing gene in this Tunisian family.     

Novel autosomal recessive nonsyndromic hearing impairment locus DFNB90 maps to 7p22.1-p15.3

A novel locus DFNB90 was mapped to 7p22.1-p15.3 by carrying out a genome scan in a multigenerational consanguineous family from Pakistan with autosomal recessive nonsyndromic hearing impairment (ARNSHI).DFNB90 is the eighth ARNSHI locus mapped to chromosome 7. A multipoint LOD score of 4.0 was obtained at a number of SNP marker loci spanning from rs1468996 (chromosome 7: 5.7 Mb) tors957960 (chromosome 7: 18.8 Mb). The 3-unit support interval and the region of homozygosity for DFNB90 spans from markers rs1553960 (chromosome 7: 4.9 Mb) to rs206198 (chromosome 7: 20.3 Mb). Candidate genes ACTB, BZW, OCM, MACC1, NXPH1, PRPS1L1, RAC1 and RPA3, which lie within the DFNB90 region, were sequenced and no potentially causal variants were identified.     

A novel locus (DFNA23) for prelingual autosomal dominant nonsyndromic hearing loss maps to 14q21-q22 in a Swiss German kindred

DFNA23, a novel locus for autosomal dominant nonsyndromic hearing loss, was identified in a Swiss German kindred. DNA samples were obtained from 22 family members in three generations: 10 with hearing impairment caused by the DFNA23 locus, 8 unaffected offspring, and 4 spouses of hearing-impaired pedigree members. In this kindred, the hearing-impaired family members have prelingual bilateral symmetrical hearing loss. All audiograms from hearing-impaired individuals displayed sloping curves, with hearing ability ranging from normal hearing to mild hearing loss in low frequencies, normal hearing to profound hearing loss in mid frequencies, and moderate to profound hearing loss in high frequencies. A conductive component existed for 50% of the hearing-impaired family members. The majority of the hearing-impaired family members did not display progression of hearing loss. The DFNA23 locus maps to 14q21-q22. Linkage analysis was carried out under a fully penetrant autosomal dominant mode of inheritance with no phenocopies. A maximum multipoint LOD score of 5.1 occurred at Marker D14S290. The 3.0-LOD unit support interval is 9.4 cM and ranged from marker D14S980 to marker D14S1046.     

A novel autosomal dominant non-syndromic deafness locus (DFNA48) maps to 12q13-q14 in a large Italian family

Non-syndromic hearing loss is the most common sensory disorder in humans; 15%-20% of cases are transmitted as a dominant trait (NSDA) with 40 loci having been mapped and 16 genes having been identified. Here, we report the mapping of a novel NSDA locus, DFNA48, to chromosome 12q13-q14 in a large multigenerational Italian family. A maximum lod score of 3.31 was obtained with marker D12S83, whereas markers D12S347 and D12S1703 defined a region of approximately 18 cM. Positional candidate genes are being screened for deafness-causing mutations.     

DFNB48, a new nonsyndromic recessive deafness locus, maps to chromosome 15q23-q25.1

Nonsyndromic deafness locus (DFNB48) segregating as an autosomal recessive trait has been mapped to the long arm of chromosome 15 in bands q23-q25.1 in five large Pakistani families. The deafness phenotype in one of these five families (PKDF245) is linked to D15S1005 with a lod score of 8.6 at =0, and there is a critical linkage interval of approximately 7 cM on the Marshfield human genetic map, bounded by microsatellite markers D15S216 (70.73 cM) and D15S1041 (77.69 cM). MYO9A, NR2E3, BBS4, and TMC3 are among the candidate genes in the DFNB48 region. The identification of another novel nonsyndromic recessive deafness locus demonstrates the high degree of locus heterogeneity for hearing impairment, particularly in the Pakistani population.     

Novel mutations in the connexin 26 gene (GJB2) that cause autosomal recessive (DFNB1) hearing loss.

Mutations in the connexin 26 (Cx26) gene (GJB2) are associated with the type of autosomal recessive nonsyndromic neurosensory deafness known as "DFNB1." Studies indicate that DFNB1 (13q11-12) causes 20% of all childhood deafness and may have a carrier rate as high as 2. 8%. This study describes the analysis of 58 multiplex families each having at least two affected children diagnosed with autosomal recessive nonsyndromic deafness. Twenty of the 58 families were observed to have mutations in both alleles of Cx26. Thirty-three of 116 chromosomes contained a 30delG allele, for a frequency of .284. This mutation was observed in 2 of 192 control chromosomes, for an estimated gene frequency of .01+/-.007. The homozygous frequency of the 30delG allele is then estimated at .0001, or 1/10,000. Given that the frequency of all childhood hearing impairment is 1/1,000 and that half of that is genetic, the specific mutation 30delG is responsible for 10% of all childhood hearing loss and for 20% of all childhood hereditary hearing loss. Six novel mutations were also observed in the affected population. The deletions detected cause frameshifts that would severely disrupt the protein structure. Three novel missense mutations, Val84Met, Val95Met, and Ser113Pro, were observed. The missense mutation 101T-->C has been reported to be a dominant allele of DFNA3, a dominant nonsyndromic hearing loss. Data further supporting the finding that this mutation does not cause dominant hearing loss are presented. This allele was found in a recessive family segregating independently from the hearing-loss phenotype and in 3 of 192 control chromosomes. These results indicate that 101T-->C is not sufficient to cause hearing loss.     

A novel locus (DFNA24) for prelingual nonprogressive autosomal dominant nonsyndromic hearing loss maps to 4q35-qter in a large Swiss German kindred

Nonsyndromic hearing loss is one of the most genetically heterogeneous traits known. A total of 30 autosomal dominant nonsyndromic hearing-loss loci have been mapped, and 11 genes have been isolated. In the majority of cases, autosomal dominant nonsyndromic hearing loss is postlingual and progressive, with the exception of hearing impairment in families in which the impairment is linked to DFNA3, DFNA8/12, and DFNA24, the novel locus described in this report. DFNA24 was identified in a large Swiss German kindred with a history of autosomal dominant hearing loss that dates back to the middle of the 19th century. The hearing-impaired individuals in this kindred have prelingual, nonprogressive, bilateral sensorineural hearing loss affecting mainly mid and high frequencies. The DFNA24 locus maps to 4q35-qter. A maximum multipoint LOD score of 11.6 was obtained at 208.1 cM at marker D4S1652. The 3.0-unit support interval for the map position of this locus ranges from 205.8 cM to 211.7 cM (5.9 cM).     

Localization of a gene for an autosomal recessive form of juvenile Parkinsonism to chromosome 6q25.2-27.

An autosomal recessive form of juvenile Parkinsonism (AR-JP) (MIM 600116) is a levodopa-responsive Parkinsonism whose pathological finding is a highly selective degeneration of dopaminergic neurons in the zona compacta of the substantia nigra. By linkage analysis of diallelic polymorphism of the Mn-superoxide dismutase gene (SOD2), we found a family with AR-JP showing perfect segregation of the disease with the SOD2 locus. By extending the linkage analysis to 13 families with AR-JP, we discovered strong evidence for the localization of the AR-JP gene at chromosome 6q25.2-27, including the SOD2 locus, with the maximal cumulative pairwise LOD scores of 7.26 and 7.71 at D6S305 (theta = .03) and D6S253 (theta = .02), respectively. Observation of obligate recombination events, as well as multipoint linkage analysis, placed the AR-JP gene in a 17-cM interval between D6S437 and D6S264. Delineation of the AR-JP gene will be an important step toward our understanding of the molecular mechanism underlying selective degeneration of the nigral neurons.     

Homozygosity mapping in consanguineous families reveals extreme heterogeneity of non-syndromic autosomal recessive mental retardation and identifies 8 novel gene loci

Autosomal recessive gene defects are arguably the most important, but least studied genetic causes of severe cognitive dysfunction. Homozygosity mapping in 78 consanguineous Iranian families with nonsyndromic autosomal recessive mental retardation (NS-ARMR) has enabled us to determine the chromosomal localization of at least 8 novel gene loci for this condition. Our data suggest that in the Iranian population NS-ARMR is very heterogeneous, and they argue against the existence of frequent gene defects that account for more than a few percent of the cases. Mohammad Mahdi Motazacker and Masoud Garshasbi have contributed equally to this work.     

Localization of a gene for autosomal recessive distal renal tubular acidosis with normal hearing (rdRTA2) to 7q33-34

Failure of distal nephrons to excrete excess acid results in the "distal renal tubular acidoses" (dRTA). Early childhood features of autosomal recessive dRTA include severe metabolic acidosis with inappropriately alkaline urine, poor growth, rickets, and renal calcification. Progressive bilateral sensorineural hearing loss (SNHL) is evident in approximately one-third of patients. We have recently identified mutations in ATP6B1, encoding the B-subunit of the collecting-duct apical proton pump, as a cause of recessive dRTA with SNHL. We now report the results of genetic analysis of 13 kindreds with recessive dRTA and normal hearing. Analysis of linkage and molecular examination of ATP6B1 indicated that mutation in ATP6B1 rarely, if ever, accounts for this phenotype, prompting a genomewide linkage search for loci underlying this trait. The results strongly supported linkage with locus heterogeneity to a segment of 7q33-34, yielding a maximum multipoint LOD score of 8.84 with 68% of kindreds linked. The LOD-3 support interval defines a 14-cM region flanked by D7S500 and D7S688. That 4 of these 13 kindreds do not support linkage to rdRTA2 and ATP6B1 implies the existence of at least one additional dRTA locus. These findings establish that genes causing recessive dRTA with normal and impaired hearing are different, and they identify, at 7q33-34, a new locus, rdRTA2, for recessive dRTA with normal hearing.     

A locus for an axonal form of autosomal recessive Charcot-Marie-Tooth disease maps to chromosome 1q21.2-q21.3.

Charcot-Marie-Tooth disease (CMT) is a heterogeneous group of disorders that affect the peripheral nervous system. Three loci are known for the autosomal dominant forms of axonal CMT (CMT2), but none have yet been identified for autosomal recessive axonal CMT (ARCMT2). We have studied a large consanguineous Moroccan ARCMT2 family with nine affected sibs. The onset of CMT was in the 2d decade in all affected individuals who presented with a severe motor and sensory neuropathy, with proximal muscle involvement occurring in some patients. After exclusion of known loci for CMT2 and for demyelinating ARCMT2, a genomewide search was performed. Evidence for linkage was found with markers on chromosome 1q. The maximum pairwise LOD score was above the threshold value of 3.00, for markers D1S514, D1S2715, D1S2777, and D1S2721, and it reached 6.10 at the loci D1S2777, D1S2721, and D1S2624, according to multipoint LOD-score analysis. These markers defined a region of homozygosity that placed the gene in a 4.4-cM interval. Moreover, a recombination event detected in an unaffected 48-year-old individual excludes the D1S506 marker, thereby reducing the interval to 1.7 cM. In addition, the P0 gene, an attractive candidate because of both its location on chromosome 1q and its role in myelin structure, was excluded by physical mapping and direct sequencing.     

A novel variant in DMXL2 gene is associated with autosomal dominant non-syndromic hearing impairment (DFNA71) in a Cameroonian family

Approximately half of congenital hearing impairment cases are inherited, with non-syndromic hearing impairment (NSHI) being the most frequent clinical entity of genetic hearing impairment cases. A family from Cameroon with NSHI was investigated by performing exome sequencing using DNA samples obtained from three family members, followed by direct Sanger sequencing in additional family members and controls participants. We identified an autosomal dominantly inherited novel missense variant [NM_001174116.2:c.918G>T; p.(Q306H)] in DMXL2 gene (MIM:612186) that co-segregates with mild to profound non-syndromic sensorineural hearing impairment . The p.(Q306H) variant which substitutes a highly conserved glutamine residue is predicted deleterious by various bioinformatics tools and is absent from several genome databases. This variant was also neither found in 121 apparently healthy controls without a family history of hearing impairment , nor 112 sporadic NSHI cases from Cameroon. There is one previous report of a large Han Chinese NSHI family that segregates a missense variant in DMXL2. The present study provides additional evidence that DMXL2 is involved in hearing impairment etiology, and we suggest DMXL2 should be considered in diagnostic hearing impairment panels.