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.     

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 locus for brachydactyly type A-1 maps to chromosome 2q35-q36

Brachydactyly type A-1 (BDA1) was, in 1903, the first recorded example of a human anomaly with Mendelian autosomal dominant inheritance. Two large families, the affected members of which were radiographed, were recruited in the study we describe here. Two-point linkage analysis for pedigree 1 (maximum LOD score [Zmax] 6.59 at recombination fraction [theta] 0.00) and for pedigree 2 (Zmax=5.53 at straight theta=0.00) mapped the locus for BDA1 in the two families to chromosome 2q. Haplotype analysis of pedigree 1 confined the locus for family 1 within an interval of <8.1 cM flanked by markers D2S2248 and D2S360, which was mapped to chromosome 2q35-q36 on the cytogenetic map. Haplotype analysis of pedigree 2 confined the locus for family 2 within an interval of <28. 8 cM flanked by markers GATA30E06 and D2S427, which was localized to chromosome 2q35-q37. The two families had no identical haplotype within the defined region, which suggests that the two families were not related.     

A locus for autosomal dominant colobomatous microphthalmia maps to chromosome 15q12-q15

Congenital microphthalmia is a common developmental ocular disorder characterized by shortened axial length. Isolated microphthalmia is clinically and genetically heterogeneous and may be inherited in an autosomal dominant, autosomal recessive, or X-linked manner. Here, we studied a five-generation family of Sephardic Jewish origin that included 38 members, of whom 7 have either unilateral or bilateral microphthalmia of variable severity inherited as an autosomal dominant trait with incomplete penetrance. After exclusion of several candidate loci, we performed a genome-scan study and demonstrated linkage to chromosome 15q12-q15. Positive LOD scores were obtained with a maximum at the D15S1007 locus (maximum LOD score 3.77, at recombination fraction 0.00). Haplotype analyses supported the location of the disease-causing gene in a 13.8-cM interval between loci D15S1002 and D15S1040.     

A progressive autosomal recessive cataract locus maps to chromosome 9q13-q22

Cataracts are the leading cause of blindness in most countries. Although most hereditary cases appear to follow an autosomal dominant pattern of inheritance, autosomal recessive inheritance has been clearly documented and is probably underrecognized. We studied a large family-from a relatively isolated geographic region-whose members were affected by autosomal recessive adult-onset pulverulent cataracts. We mapped the disease locus to a 14-cM interval at a novel disease locus, 9q13-q22 (between markers D9S1123 and D9S257), with a LOD score of 4.7. The study of this progressive and age-related cataract phenotype may provide insight into the cause of the more common sporadic form of age-related cataracts.     

A locus for migraine without aura maps on chromosome 14q21.2-q22.3

Migraine is a common and disabling neurological disease of unknown origin characterized by a remarkable clinical variability. It shows strong familial aggregation, suggesting that genetic factors are involved in its pathogenesis. Different approaches have been used to elucidate this hereditary component, but a unique transmission model and causative gene(s) have not yet been identified. We report clinical and molecular data from a large Italian pedigree in which migraine without aura (MO) segregates as an autosomal dominant trait. After exclusion of any association between MO and the known familial hemiplegic migraine and migraine with aura loci, we performed a genomewide linkage analysis using 482 polymorphic microsatellite markers. We obtained significant evidence of linkage between the MO phenotype and the marker D14S978 on 14q22.1 (maximum two-point LOD score of 3.70, at a recombination fraction of 0.01). Multipoint parametric analysis (maximum LOD score of 5.25 between markers D14S976 and D14S978) and haplotype construction showed strong evidence of linkage in a region of 10 cM flanked by markers D14S1027 and D14S980 on chromosome 14q21.2-q22.3. These results indicate the first evidence of a genetic locus associated with MO on chromosome 14.     

The autosomal recessive nonsyndromic deafness locus DFNB72 is located on chromosome 19p13.3

We ascertained three consanguineous Pakistani families (PKDF291, PKDF335 and PKDF793) segregating nonsyndromic recessive hearing loss. The hearing loss segregating in PKDF335 and PKDF793 is moderate to severe, whereas it is profound in PKDF291. The maximum two-point LOD scores are 3.01 (D19S1034), 3.85 (D19S894) and 3.71 (D19S894) for PKDF291, PKDF335 and PKDF793, respectively. Haplotype analyses of the three families define a 1.16 Mb region of overlap of the homozygous linkage intervals bounded by markers D19S216 (20.01 cM) and D19S1034 (20.75 cM). These results define a novel locus, DFNB72, on chromosome 19p13.3. There are at least 22 genes in the 1.16 Mb interval, including PTPRS, ZNRF4 and CAPS. We identified no pathogenic variants in the exons and flanking intronic sequences of these three genes in affected members of the DFNB72 families. DFNB72 is telomeric to DFNB68, the only other known deafness locus with statistically significant support for linkage to chromosome 19p.     

A novel locus for distal motor neuron degeneration maps to chromosome 7q34-q36

The motor neuron diseases (MND) are a group of related neurodegenerative diseases that cause the relative selective progressive death of motor neurons. These diseases range from slowly progressive forms including hereditary motor neuropathy (HMN), to the rapidly progressive disorder amyotrophic lateral sclerosis (ALS). There is clinical and genetic overlap among these MNDs, implicating shared pathogenic mechanisms. We recruited a large family with a MND that was previously described as juvenile ALS and distal HMN. We identified a novel MND/HMN locus on chromosome 7q34-q36 following a genome-wide scan for linkage in this family. The disease causing mutation maps to a 26.2 cM (12.3 Mb) interval flanked by D7S2513 and D7S637 on chromosome 7q34-q36. Recombinant haplotype analysis including unaffected individuals suggests that the refined candidate interval spans 14.3 cM (6.3 Mb) flanked by D7S2511 and D7S798. One gene in the candidate interval, CDK5, was selected for immediate mutation analysis based upon its known association with an ALS-like phenotype in mice however, no mutations were identified. Identification of genes causing familial MND will lead to a greater understanding of the biological basis of both familial and sporadic motor neuron degeneration including ALS. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

African American hypertensive nephropathy maps to a new locus on chromosome 9q31-q32

Hypertensive nephropathy (HN) and focal segmental glomerulosclerosis (FSGS) are significant causes of end-stage renal disease (ESRD), but no genes or loci have been associated with this phenotype among African Americans, a group at high risk. We performed a genomewide linkage scan with approximately 400 microsatellite markers on 23 individuals of a large four-generation African American family with 18 affected individuals (7 with ESRD), in which the 13-year-old proband (also with ESRD) presented with hypertension and proteinuria (2-4 g/day) and underwent a kidney biopsy that revealed FSGS-like lesions with arteriolar thickening. A genomewide scan revealed LOD scores of >2.5 for markers on chromosomes 3 and 9, and fine mapping was performed on 5 additional members (total 28 members) that showed a maximum multipoint LOD score of 5.4 in the 9q31-q32 region, under an autosomal dominant model with 99% penetrance. This 8-cM (6-Mb) region is flanked by markers D9S172 and D9S105, and further candidate gene sequencing studies excluded the coding regions of three genes (ACTL7A, ACTL7B, and CTNNAL1). To our knowledge, this is the first report of a locus, denoted as "HNP1," for the HN/FSGS phenotype in a large African American family with dominantly inherited nephropathy characterized by ESRD, hypertension, and some features of FSGS.     

A new locus for hereditary gingival fibromatosis (GINGF2) maps to 5q13-q22

Gingival fibromatosis (GINGF) is an oral disorder characterized by enlargement of the gingiva. It occurs either as the sole phenotype or combined with other symptoms. Thus far, one GINGF locus has been mapped on chromosome 2, at 2p21, and a second possible locus has been mapped to 2p13. However, the genes responsible for this disorder have not been elucidated. We identified a four-generation Chinese GINGF family in which the disease manifests within 1 year after birth. After exclusion of the two known GINGF loci in this family, we performed a genome-wide search to map the chromosome location of the responsible gene. We identified a new locus, GINGF2, on chromosome 5q13-q22 with a maximum two-point lod score of 4.31 at D5S1721 (theta = 0.00). Haplotype analysis placed the critical region in the interval defined by D5S1491 and D5S1453. Within this region, calcium/calmodulin-dependent protein kinase IV (CAMK4) is a strong candidate.     

A new susceptibility locus for hypospadias on chromosome 7q32.2-q36.1

Hypospadias is a common malformation (1/300 boys) where the urethra opens on the ventral side of the penis. It is considered a complex disorder with both genetic and environmental factors involved in the pathogenesis. To identify the chromosomal loci involved in the pathogenesis of hypospadias, we performed a genome-wide linkage analysis in a three-generational family showing autosomal dominant inheritance of hypospadias. Fifteen individuals, whereof seven affected, were genotyped within a total of 426 microsatellite markers and the genotyping results were analyzed using parametric and non-parametric linkage analyses. The genome-wide linkage analysis and subsequent fine mapping gave a maximum linkage in both parametric (LOD score 2.71) and non-parametric (NPL score 5.01) single-point analyses for marker D7S640. A susceptibility haplotype shared by all affected boys was identified with the centromeric and telomeric boundaries defined by markers D7S2519 and D7S2442, respectively. This suggests a novel hypospadias locus at chromosome 7q32.2-q36.1 that encompasses 18.2 Mb (25 cM) and harbors hundreds of genes. Mutation analysis of two genes within the region, the AKR1D1 (aldo-keto reductase family 1, member D1) gene involved in the androgen pathway and the PTN gene coding for pleiotrophin, an embryonic differentiation and growth factor, was performed but without putative findings.     

The tyrosinase-positive oculocutaneous albinism locus maps to chromosome 15q11.2-q12.

Tyrosinase-positive oculocutaneous albinism (ty-pos OCA), an autosomal recessive disorder of the melanin biosynthetic pathway, is the most common type of albinism occurring worldwide. In southern African Bantu-speaking negroids it has an overall prevalence of about 1/3,900. Since the basic biochemical defect is unknown, a linkage study with candidate loci, candidate chromosomal regions, and random loci was undertaken. The ty-pos OCA locus was found to be linked to two arbitrary loci, D15S10 and D15S13, in the Prader-Willi/Angelman chromosomal region on chromosome 15q11.2-q12. The pink-eyed dilute locus, p, on mouse chromosome 7, maps close to a region of homology on human chromosome 15q, and we postulate that the ty-pos OCA and p loci are homologous.     

A gene locus responsible for dyschromatosis symmetrica hereditaria (DSH) maps to chromosome 6q24.2-q25.2

Dyschromatosis symmetrica hereditaria (DSH) is a hereditary skin disease characterized by the presence of hyperpigmented and hypopigmented macules on extremities and face. The gene, or even its chromosomal location, for DSH has not yet been identified. In this study, two Chinese families with DSH were identified and subjected to a genomewide screen for linkage analysis. Two-point linkage analysis for pedigree A (maximum LOD score [Z(max)] = 7.28 at recombination fraction [theta] = 0.00) and pedigree B (Z(max) = 2.41 at theta = 0.00) mapped the locus for DSH in the two families to chromosome 6q. Subsequent multipoint analysis of the two families also provided additional support for the DSH gene being located within the region 6q24.2-q25.2, with Z(max) = 10.64. Haplotype analysis confined the locus within an interval of 10.2 Mbp, flanked by markers D6S1703 and D6S1708. The two families had no identical haplotype within the defined region, which suggests that the two families were different in origin. Further work on identification of the gene for DSH will open new avenues to exploration of the genetics of pigmentation.     

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.     

Juvenile hemochromatosis locus maps to chromosome 1q

Juvenile hemochromatosis (JH) is an autosomal recessive disorder that leads to severe iron loading in the 2d to 3d decade of life. Affected members in families with JH do not show linkage to chromosome 6p and do not have mutations in the HFE gene that lead to the common hereditary hemochromatosis. In this study we performed a genomewide search to map the JH locus in nine families: six consanguineous and three with multiple affected patients. This strategy allowed us to identify the JH locus on the long arm of chromosome 1. A maximum LOD score of 5.75 at a recombination fraction of 0 was detected with marker D1S498, and a LOD score of 5. 16 at a recombination fraction of 0 was detected for marker D1S2344. Homozygosity mapping in consanguineous families defined the limits of the candidate region in an approximately 4-cM interval between markers D1S442 and D1S2347. Analysis of genes mapped in this interval excluded obvious candidates. The JH locus does not correspond to the chromosomal localization of any known gene involved in iron metabolism. These findings provide a means to recognize, at an early age, patients in affected families. They also provide a starting point for the identification of the affected gene by positional cloning.