Mapping of DFNB12, a gene for a non-syndromal autosomal recessive deafness, to chromosome 10q21-22

We report here, the localization of a new recessive non-syndromal deafness gene (DFNB12) to 10q21-22 by linkage analysis, of a Sunni family. Affected individuals suffer from congenital profound sensorineural hearing loss. A maximum LOD score of 6.40 (theta = 0.00) was obtained with locus D10S535. Analysis of patients carrying recombinations mapped the gene distal to D10S529 and proximal to D10S532, delineating an interval between 11 and 15 cM. Three deaf mouse mutants Jackson circler (jc), Waltzer (v) and Ames waltzer (av) have been localized to the homologous murine region on chromosome 10. Each of these mouse mutants is a candidate mouse model for the DFNB12- associated hearing impairment.      

Localization of a novel gene for nonsyndromic hearing loss (DFNB17) to chromosome region 7q31

Autosomal recessive nonsyndromic hearing loss (ARNSHL) is the most common form of hereditary hearing impairment (HHI). To date, 16 different loci have been reported, making ARNSHL an extremely heterogeneous disorder. One of these loci, DFNB4, was mapped to a 5-cM interval of 7q31 in a large Middle-Eastern Druze family. This interval also includes the gene for Pendred syndrome. We report on three new families with HHI from the Madras region of southern India that demonstrate linkage to 7q. Their pedigrees are compatible with autosomal recessive inheritance. Furthermore, the largest family identifies a novel locus (DFNB17) telomeric to the DFNB4 and Pendred intervals. A 3-cM region of homozygosity by descent between markers D7S486 and D7S2529 is present in all affected individuals in this family and generates a multipoint LOD score of 4.24. The two other families map to the previously reported DFNB4 region but have insufficient power to attain significant LOD scores. However, mutations in the Pendred syndrome gene are present in one of these families. Am. J. Med. Genet. 78:107–113, 1998. © 1998 Wiley-Liss, Inc.     

DFNB31, a recessive form of sensorineural hearing loss, maps to chromosome 9q32-34

We report the identification of a novel locus responsible for an autosomal recessive form of hearing loss (DFNB) segregating in a Palestinian consanguineous family from Jordan. The affected individuals suffer from profound prelingual sensorineural hearing impairment. A genetic linkage with polymorphic markers surrounding D9S1776 was detected, thereby identifying a novel deafness locus, DFNB31. This locus could be assigned to a 9q32-34 region of 15 cM between markers D9S289 and D9S1881. The whirler (wi) mouse mutant, characterised by deafness and circling behaviour, maps to the corresponding region on the murine chromosome 4, thus suggesting that DFNB31 and whirler may result from orthologous gene defects.     

Linkage of 'pure' autosomal recessive familial spastic paraplegia to chromosome 8 markers and evidence of genetic locus heterogeneity

‘Pure’ familial spastic paraplegias (FSP) are neuro-degenerativedisorders that are clinically characterized by progressive spastlcityof the lower limbs and are inherited as autosomal dominant (DFSP)or autosomal recessive (RFSP) traits. The primary defect inFSP Is unknown. Genetic linkage analysis was applied to fiveRFSP families from Tunisia. In four of these five families tightlinkage of the RFSP locus was established to the chromosome8 markers, D8S260, D8S166, D8S285, PLAT, and D8S279. The RFSPlocus in the fifth family was not linked to these markers whichprovided evidence of genetic locus heterogeneity In RFSP. Identificationof the RFSP gene on chromosome 8 will help in understandingthe genetic factors in motor neuron degeneration.     

A new locus for autosomal recessive non-syndromal sensorineural hearing impairment (DFNB27) on chromosome 2q23-q31

Non-syndromic sensorineural deafness is an extremely genetically heterogeneous condition. We have used autozygosity mapping in a large consanguineous United Arab Emirate family to identify a novel locus for autosomal recessive non-syndromic sensorineural deafness, DFNB27, on chromosome 2q23-q31, with a maximum two-point lod score of 5.18 at theta = 0 for marker D2S2257. The DFNB27 locus extends over a 17 cM region between D2S2157 and D2S2273, and may overlap the DFNA16 locus for dominantly inherited, fluctuating, progressive non-syndromal hearing loss. However, genotype data suggests that the locus is likely to be refined to between D2S326 and D2S2273 and thus distinct from the DFNA16 locus.     

Linkage of a locus (CMT4A) for autosomal recessive Charcot-Marie-Tooth disease to chromosome 8q

Autosomal recessive Charcot-Marie-Tooth (CMT) disease (CMT4)is a complex group of severe childhood motor and sensory neuropathies,characterized by an early age of onset with rapidly progressivedistal limb weakness and atrophy. One subgroup designated CMT4type A (CMT4A) was selected from a series of Tunisian CMT4 familiesaccording to the following electrophysiological and pathologicalcriteria: slow motor nerve conduction velocity (MCV), severehypomyelination upon nerve biopsy with basal lamina onion bulbsand no myeiin outfolding. In an attempt to localize the CMT4Alocus, we studied four inbred families with 13 affected patients.Significant evidence for linkage was found for several markersfrom chromosome 8q13–21.1 (D8S279, D8S164, D8S286, D8S84,D8S275 and D8S167). An overall two point peak lod score of z(     

Autosomal recessive non-syndromic deafness locus (DFNB8) maps on chromosome 21q22 in a large consanguineous kindred from Pakistan

Autosomal recessive childhood-onset non-syndromic deafness is one of the most frequent forms of inherited hearing impairment. Recently five different chromosomal regions, 7q31, 11q13.5, 13q12, 14q and the pericentromeric region of chromosome 17, have been shown to harbour disease loci for this type of neurosensory deafness. We have studied a large family from Pakistan, containing several consanguineous marriages and segregating for a recessive non-syndromic childhood-onset deafness. Linkage analysis mapped the disease locus (DFNB8) on the distal long arm of chromosome 21, most likely between D21S212 and D21S1225 with the highest lod score of 7.31 at theta = 0.00 for D21S1575 on 21q22.3.      

DFNB39, a recessive form of sensorineural hearing impairment, maps to chromosome 7q11.22-q21.12

This article describes the identification of a novel locus (DFNB39) responsible for an autosomal recessive form of hearing loss segregating in a Pakistani consanguineous family. The hearing impaired members of this family present with profound prelingual sensorineural hearing impairment and use sign language for communications. Linkage was established to microsatellite markers located on chromosome 7q with a maximum multipoint lod score of 3.8. The region of homozygosity spans a 19 cM region that is bounded by markers D7S3046 and D7S644.     

Linkage of hereditary haemorrhagic telangiectasia to chromosome 9q34 and evidence for locus heterogeneity.

Hereditary haemorrhagic telangiectasia (HHT) is an autosomal dominant disorder with unknown pathophysiology that is characterised by arteriovenous lesions and recurrent haemorrhage in virtually every organ. Linkage of HHT to markers on chromosome 9q has recently been reported. In this study we report confirmation of this localisation in three unrelated families of Dutch origin. A fourth unrelated HHT family, in which considerably fewer pulmonary arteriovenous malformations (PAVM) were present, yielded evidence for non-linkage to this region. We conclude that HHT is a genetically heterogeneous disorder and our results indicate that the presence of PAVM may be more common in patients with a chromosome 9 linked form of HHT than in patients with the non-linked form.     

REPORTS: Linkage of Pfeiffer syndrome to chromosome 8 centromere and evidence for genetic heterogeneity

Pfeiffer syndrome (PS) Is an autosomal dominant disorder characterizedby cranlosynostosis, mldfaclal hypoplasia, and broad thumbsand great toes. We examined 129 Individuals from 11 familieswith PS and performed linkage studies using microsatellite markersspanning the entire genome. Strongest support for linkage waswith DNA markers (D8S255, GATA8G08) from chromosome 8. Obligatecrossovers exclude close linkage to this region in six families,and there was significant evidence for genetic heterogeneity.A multipoint lod score of 7.15 was obtained In five families.The 11 cM Interval between D8S278 and D8S285 contains one genefor PS and also spans the centromere of chromosome 8.     

Non-syndromic recessive deafness in Jordan: mapping of a new locus to chromosome 9q34.3 and prevalence of DFNB1 mutations

Non-syndromic recessive deafness (NSRD) is the most commonly encountered form of hereditary hearing loss. The majority of NSRD cases in the Mediterranean area are linked to the DFNB1 locus (the connexin 26 GJB2 gene). Unrelated NSRD patients issued from 68 Jordanian families, were tested for mutations of the GJB2 gene by sequencing. Sixteen per cent of the families tested were linked to the DFNB1 locus. The 35delG was the only GJB2 mutation detected in these families. One of these families, presenting with four affected members and not linked to the gene, was subjected to a genome-wide search and was found to be mapped to 9q34.3 with a multipoint lodscore of 3.9. One candidate gene in the interval, coding for the chloride intracellular channel 3, CLIC3, was tested and excluded. The identification of a new NSRD locus, DFNB33, in one Jordanian family, shows the wide genetic heterogeneity that characterizes hearing impairment and the genetic diversity in Middle-Eastern populations.     

Mapping of a novel autosomal recessive nonsyndromic deafness locus (DFNB46) to chromosome 18p11.32-p11.31

Hereditary nonsyndromic deafness (NSD) is extremely heterogeneous. Autosomal recessive (AR) forms account for approximately 75% of genetic cases. To date, over 40 ARNSD loci have been mapped. A novel locus (DFNB46) for ARNSD was mapped to chromosome 18p11.32-p11.31 in a five-generation Pakistani family. A 10 cM genome-wide scan and fine mapping was carried out using microsatellite markers. A maximum multipoint LOD score of 3.8 was obtained at two markers, D18S481 and D18S1370. The three-unit support interval is flanked by markers D18S59 and D18S391, corresponds to a 17.6 cM region according to the deCode genetic map and spans 5.8 Mb on the sequence-based physical map.     

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.     

A novel autosomal recessive nonsyndromic hearing impairment locus (DFNB42) maps to chromosome 3q13.31-q22.3

A consanguineous family with autosomal recessive nonsyndromic hearing impairment (NSHI) was ascertained in Pakistan and displayed significant evidence of linkage to 3q13.31-q22.3. The novel locus (DFNB42) segregating in this kindred, maps to a 21.6 cM region according to a genetic map constructed using data from both the deCode and Marshfield genetic maps. This region of homozygosity is flanked by markers D3S1278 and D3S2453. A maximum multipoint LOD score of 3.72 was obtained at marker D3S4523. DFNB42 represents the third autosomal recessive NSHI locus to map to chromosome 3.     

Four novel TMC1 (DFNB7/DFNB11) mutations in Turkish patients with congenital autosomal recessive nonsyndromic hearing loss

Mutations in the transmembrane channel-like gene 1 (TMC1) cause prelingual autosomal recessive (DFNB7/11) and postlingual progressive autosomal dominant (DFNA36) nonsyndromic hearing loss. To determine the genetic causes of autosomal recessive nonsyndromic hearing loss (ARNSHL) in the northeast and east of Turkey, 65 unrelated families without mutations in the protein coding region of the GJB2 (GJB2-negative) were analyzed. A genomewide scan for homozygosity and linkage analysis in one of these families revealed a 13.2 cM critical region between D9S273 and D9S153 at chromosome 9p13.2-q21.31 with a maximum two-point lod score of 4.00 at theta=0.0 for marker D9S175. TMC1 is in this critical region. Homozygosity screening with intragenic markers for TMC1 in the remaining 64 families suggested involvement of this gene in three additional families. Subsequent sequencing of TMC1 in these four families revealed four novel homozygous mutations, c.776A>G [p.Tyr259Cys], c.821C>T [p.Pro274Leu], c.1334G>A [p.Arg445His], and c.1083_1087delCAGAT [p.Arg362ProfrX6]. Our results indicate that TMC1 mutations account for at least 6% (4/65) of ARNSHL in GJB2-negative Turkish families from the northeast and east of Turkey.     

A new locus for non-syndromal, autosomal recessive, sensorineural hearing loss (DFNB16) maps to human chromosome 15q21-q22.

Non-syndromal, recessive deafness (NSRD) is the most common form of inherited deafness or hearing impairment in humans. NSRD is genetically heterogeneous and it has been estimated that as many as 35 different loci may be involved. We report the mapping of a novel locus for autosomal recessive, non-syndromal deafness (DFNB16) in three consanguineous families originating from Pakistan and the Middle East. Using multipoint analysis (HOMOZ/MAPMAKER) a maximum combined lod score of 6.5 was obtained for the interval D15S1039-D15S123. Recombination events and haplotype analysis define a 12-14 cM critical region between the markers D15S1039 and D15S155 on chromosome 15q15-q21.     

Linkage of aggressive prostate cancer to chromosome 7q31-33 in German prostate cancer families

It has been suggested that chromosome 7q32 contains genes that influence the progression of prostate cancer from latent to invasive disease. In an attempt to confirm this linkage to prostate cancer aggressiveness, 100 German prostate cancer families were genotyped using a panel of eight polymorphic markers on chromosome 7q. We used a multipoint allele sharing method based upon a likelihood ratio test implemented in GENEHUNTERPLUS v1.2 in order to calculate the nonparametric Z(lr) and the associated LOD scores. We applied the aggressiveness of prostate cancer given by the pathological tumour grade of each individual, and the mean age of onset of a family as covariates, and constructed two weighted models. The first (weight(0-1) model) puts weights on families with at least two cases of GIII prostate cancer. The second (weight(0-2) model) also adds weights to families with early and late onset cancer respectively. The unweighted analysis gave no evidence of linkage to chromosome 7q. The Z(lr) scores increased when including the covariates, to 2.60 (P=0.005) using the weight(0-1) and to 3.02 (P=0.001) using the weight(0-2) model for late onset prostate cancer. The associated LOD scores were respectively 1.47 (P=0.009) and 1.98 (P=0.002). The markers that gave most evidence for linkage were exactly in the range of the published prostate cancer aggressiveness region. Our results support a widespread relevance of this locus and suggest that aggressive and late onset prostate cancer is linked to chromosme 7q31-33 in the German population.     

Systemic lupus erythematosus (SLE) and chromosome 16: confirmation of linkage to 16q12-13 and evidence for genetic heterogeneity

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease with significant morbidity and mortality, characterized by remarkable clinical variability with unknown etiology. Genetic contribution to the development of SLE is well established. Recently, we found evidence (P<0.004) of linkage at 16p13 and 16q12-13 in a genome scan based on 37 Hispanic families. The main objective of this study is to replicate and confirm the linkage at these two genomic locations in two large independent replication data sets designated as, group-1 and group-2, consisting of 172 and 120 multiplex SLE families, respectively. We have found a significant evidence of linkage with high heterogeneity (HLOD=4.85, alpha=35%) at 16q12-13 in group-2. Other independent research groups also reported the SLE susceptibility at or close to 16q12-13 previously. Therefore, independent published reports, together with our initial linkage with Hispanics and followed by significant evidence from group-2, provide a strong and confirmed evidence for an SLE susceptibility locus at 16q12-13.