A novel genetic locus for juvenile myoclonic epilepsy at chromosome 5q12–q14

Juvenile myoclonic epilepsy is a clinically well-defined, age-related common idiopathic generalized epilepsy syndrome with substantial genetic basis to its etiology. We report identification of a novel epilepsy locus at chromosome 5q12–q14 in a family exhibiting autosomal dominant form of juvenile myoclonic epilepsy from south India. The highest two-point LOD score of 3.3344 was obtained for the microsatellite markers D5S641 and D5S459 at 5q14. Centromeric and telomeric chromosomal boundaries of the locus were defined by D5S624 and D5S428, respectively. The 5q12–q14 locus encompasses about 25 megabases of the genomic region and harbours several candidate genes. Further work involving a detailed mutational analysis of the locus, to isolate the gene responsible for the epilepsy disorder in the family, shall help enhance our understanding of molecular basis of epilepsy disorders.     

Localization of a novel locus for alopecia with mental retardation syndrome to chromosome 3q26.33–q27.3

Alopecia with mental retardation syndrome is a rare autosomal recessive disorder characterized clinically by total or partial alopecia and mental retardation. In an effort to understand the molecular bases of this form of alopecia syndrome, large Pakistani consanguineous kindred with multiple affected individuals has been ascertained from a remote region in Pakistan. Genome wide scan mapped the disease locus on chromosome 3q26.33–q27.3. A maximum two-point LOD score of 3.05 (θ=0.0) was obtained at marker D3S3583. Maximum multipoint LOD score exceeding 5.0, obtained with several markers, supported the linkage. Recombination events observed in affected individuals localized the disease locus between markers D3S1232 and D3S2436, spanning 11.49-cM region on chromosome 3q26.33–q27.3. Sequence analysis of a candidate gene ETS variant gene 5 from DNA samples of two affected individuals of the family revealed no mutation.     

A locus for familial generalized lentiginosis without systemic involvement maps to chromosome 4q21.1–q22.3

Generalized lentiginosis (GL) is characterized by widespread lentigines without associated noncutaneous abnormalities. In this study we performed a genome-wide linkage search in a Chinese family with GL and localized the familial GL locus to chromosome 4q21.1–q22.3, with a maximum two-point LOD score of 3.01 for D4S395 and D4S423 at a recombination fraction of 0. Multipoint analysis (maximum LOD score of 5.08 between markers D4S395 and D4S1563) and haplotype construction showed strong evidence of linkage in a region of 20 Mb flanked by markers D4S2915 and D4S1560 on chromosome 4q21.1–q22.3. This is the first report of linkage for GL, and it will provide further insight into the controversy of whether GL is an entity distinct from LEOPARD syndrome.Qinghe Xing and Xiangdong Chen contributed equally to this work     

A locus for juvenile myoclonic epilepsy maps to 2q33–q36

We performed a whole genome linkage analysis in a three-generation south Indian family with multiple members affected with juvenile myoclonic epilepsy (JME). The maximum two-point LOD score obtained was 3.32 at recombination fraction (θ) = 0 for D2S2248. The highest multipoint score of 3.59 was observed for the genomic interval between D2S2322 and D2S2228 at the chromosomal region 2q33–q36. Proximal and distal boundaries of the critical genetic interval were defined by D2S116 and D2S2390, respectively. A 24-Mb haplotype was found to co-segregate with JME in the family. While any potentially causative variant in the functional candidate genes, SLC4A3, SLC23A3, SLC11A1 and KCNE4, was not detected, we propose to examine brain-expressed NRP2, MAP2, PAX3, GPR1, TNS1 and DNPEP, and other such positional candidate genes to identify the disease-causing gene for the disorder.     

Identification of an autosomal recessive stuttering locus on chromosome 3q13.2–3q13.33

Stuttering is a common speech disorder with substantial genetic contributions. To better understand the genetic factors involved in stuttering, we performed a genome-wide linkage study in a newly-ascertained consanguineous stuttering family from Pakistan. A linkage scan in this family using parametric linkage analysis revealed significant linkage only on chromosome 3q13.2–3q13.33, with a maximum two-point LOD score of 4.23 under an autosomal recessive model of inheritance.     

Mapping of a novel autosomal recessive hypotrichosis locus on chromosome 10q11.23–22.3

Autosomal recessive hypotrichosis is a rare form of human genetic disorder characterized by sparse to absent hair on scalp and rest of the body of affected individuals. Over the past few years at least five autosomal recessive forms of hypotrichosis loci have been mapped on different human chromosomes. In the present study, we report localization of another novel autosomal recessive hypotrichosis locus on human chromosome 10q11.23–22.3 in a four generation consanguineous Pakistani family. All the four patients in the family showed typical features of hereditary hypotrichosis including sparse hair on the scalp and rest of the body. Human genome scan using highly polymorphic microsatellite markers mapped the disease locus to a large region on chromosome 10. This novel locus maps to 29.81 cM (28.5 Mb) region, flanked by markers D10S538 and D10S2327 on chromosome 10q11.23–22.3. A maximum multipoint LOD score of 3.26 was obtained with several markers in this region. DNA sequence analysis of exons and splice-junction sites of four putative candidate genes (P4HA1, ZNF365, ZMYND17, MYST4), located in the linkage interval, were sequenced but were negative for functional sequence variants.     

A novel locus for autosomal dominant nonsyndromic hearing loss (DFNA44) maps to chromosome 3q28–29

Hereditary non-syndromic sensorineural hearing loss (NSSHL) is a genetically highly heterogeneous group of disorders. Autosomal dominant forms account for up to 20% of cases. To date, 39 loci have been identified by linkage analysis of affected families that segregate NSSHL forms in the autosomal dominant mode (DFNA). Investigation of a large Spanish pedigree with autosomal dominant inheritance of bilateral and progressive NSSHL of postlingual onset excluded linkage to known DFNA loci and, in a subsequent genome-wide scan, the disorder locus was mapped to 3q28-29. A maximum two-point LOD score of 4.36 at theta=0 was obtained for marker D3S1601. Haplotype analysis placed the novel locus, DFNA44, within a 3-cM genetic interval defined by markers D3S1314 and D3S2418. Heteroduplex analysis and DNA sequencing of coding regions and exon/intron boundaries of two genes (CLDN16 and FGF12) in this interval did not reveal disease-causing mutations.     

A comprehensive resequence analysis of the KLK15–KLK3–KLK2 locus on chromosome 19q13.33

Single nucleotide polymorphisms (SNPs) in the KLK3 gene on chromosome 19q13.33 are associated with serum prostate-specific antigen (PSA) levels. Recent genome wide association studies of prostate cancer have yielded conflicting results for association of the same SNPs with prostate cancer risk. Since the KLK3 gene encodes the PSA protein that forms the basis for a widely used screening test for prostate cancer, it is critical to fully characterize genetic variation in this region and assess its relationship with the risk of prostate cancer. We have conducted a next-generation sequence analysis in 78 individuals of European ancestry to characterize common (minor allele frequency, MAF >1%) genetic variation in a 56 kb region on chromosome 19q13.33 centered on the KLK3 gene (chr19:56,019,829–56,076,043 bps). We identified 555 polymorphic loci in the process including 116 novel SNPs and 182 novel insertion/deletion polymorphisms (indels). Based on tagging analysis, 144 loci are necessary to tag the region at an r ² threshold of 0.8 and MAF of 1% or higher, while 86 loci are required to tag the region at an r ² threshold of 0.8 and MAF >5%. Our sequence data augments coverage by 35 and 78% as compared to variants in dbSNP and HapMap, respectively. We observed six non-synonymous amino acid or frame shift changes in the KLK3 gene and three changes in each of the neighboring genes, KLK15 and KLK2. Our study has generated a detailed map of common genetic variation in the genomic region surrounding the KLK3 gene, which should be useful for fine-mapping the association signal as well as determining the contribution of this locus to prostate cancer risk and/or regulation of PSA expression.     

Linkage and LOH studies in 19 cylindromatosis families show no evidence of genetic heterogeneity and refine the CYLD locus on chromosome 16q12–q13

Familial cylindromatosis is an autosomal dominant predisposition to multiple neoplasms of the skin appendages. The susceptibility gene has previously been mapped to chromosome 16q12-q13 and has features of a recessive oncogene/tumour suppressor gene. We have now evaluated 19 families with this disease by a combination of genetic linkage analysis and loss of heterozygosity in cylindromas from affected individuals. All 15 informative families show linkage to this locus, providing no evidence for genetic heterogeneity. Recombinant mapping has placed the gene in an interval of approximately 1 Mb. There is no evidence, between families, of haplotype sharing that might be indicative of common founder mutations.     

A novel locus for Usher syndrome type I, USH1G, maps to chromosome 17q24–25

Usher syndrome (USH) is an autosomal recessive disorder associated with sensorineural hearing impairment and progressive visual loss attributable to retinitis pigmentosa. This syndrome is both clinically and genetically heterogeneous. Three clinical types have been described of which type I (USH1) is the most severe. Six USH1 loci have been identified. We report a Palestinian consanguineous family from Jordan with three affected children. In view of the combination of profound hearing loss, vestibular dysfunction, and retinitis pigmentosa in the patients, we classified the disease as USH1. Linkage analysis excluded the involvement of any of the known USH1 loci. A genome-wide screening allowed us to map this novel locus, USH1G, in a 23-cM interval on chromosome 17q24-25. The USH1G interval overlaps the intervals for two dominant forms of isolated hearing loss, namely DFNA20 and DFNA26. Since several examples have been reported of syndromic and isolated forms of deafness being allelic, USH1G, DFNA20, and DFNA26 might result from alterations of the same gene. Finally, a mouse mutant, jackson shaker ( js), with deafness and circling behavior has been mapped to the murine homologous region on chromosome 11.     

A 1.35 Mb DNA fragment is inserted into the DHMN1 locus on chromosome 7q34–q36.2

Distal hereditary motor neuropathies predominantly affect the motor neurons of the peripheral nervous system leading to chronic disability. Using whole genome sequencing (WGS) we have identified a novel structural variation (SV) within the distal hereditary motor neuropathy locus on chromosome 7q34–q36.2 (DHMN1). The SV involves the insertion of a 1.35 Mb DNA fragment into the DHMN1 disease locus. The source of the inserted sequence is 2.3 Mb distal to the disease locus at chromosome 7q36.3. The insertion involves the duplication of five genes (LOC389602, RNF32, LMBR1, NOM1, MNX1) and partial duplication of UBE3C. The genomic structure of genes within the DHMN1 locus are not disrupted by the insertion and no disease causing point mutations within the locus were identified. This suggests the novel SV is the most likely DNA mutation disrupting the DHMN1 locus. Due to the size and position of the DNA insertion, the gene(s) directly affected by the genomic re-arrangement remains elusive. Our finding represents a new genetic cause for hereditary motor neuropathies and highlights the growing importance of interrogating the non-coding genome for SV mutations in families which have been excluded for genome wide coding mutations.     

Genetic variation at the matrix metalloproteinase-9 locus on chromosome 20q12.2–13.1

Allelic association methods are better suited than linkage analysis for mapping of susceptibility genes that confer modest increases in risk in complex diseases. In both family- and population-based association studies, it is very useful to have prior knowledge of all sequence variants and the degree of linkage disequilibrium in a candidate gene region. In this study, we scanned sequence variants in a 2.2-kb promoter sequence and all 13 exons (totalling 3.3 kb) of the matrix metalloproteinase-9 gene, which is associated with coronary heart disease and a candidate for other diseases involving connective tissue remodelling, such as cancer metastasis. The sequences had a total of ten variable sites, four in the promoter, five in the coding region (three of which alter the amino acid encoded) and one in the 3' untranslated sequence. Sequence inspection suggests that some of the variants will have a functional impact on either level of expression or enzymatic activity. Tight linkage disequilibrium was detected between variants across the entire length of the gene (approximately 9 kb), and frequencies of different haplotypes were determined. The data provide an essential tool for studies of the possible contribution of genetic variation at the matrix metalloproteinase-9 locus to genetically determined susceptibility to a number of important diseases. The results also provide experimental data on the extent of linkage disequilibrium in the general population, which is yet to be resolved.     

Fine mapping of familial prostate cancer families narrows the interval for a susceptibility locus on chromosome 22q12.3 to 1.36 Mb

Genetic studies suggest that hereditary prostate cancer is a genetically heterogeneous disease with multiple contributing loci. Studies of high-risk prostate cancer families selected for aggressive disease, analysis of large multigenerational families, and a meta-analysis from the International Consortium for Prostate Cancer Genetics (ICPCG), all highlight chromosome 22q12.3 as a susceptibility locus with strong statistical significance. Recently, two publications have narrowed the 22q12.3 locus to a 2.18 Mb interval using 54 high-risk families from the ICPCG collaboration, as defined by three recombination events on either side of the locus. In this paper, we present the results from fine mapping studies at 22q12.3 using both haplotype and recombination data from 42 high-risk families contributed from the Mayo Clinic and the Prostate Cancer Genetic Research Study (PROGRESS) mapping studies. No clear consensus interval is present when all families are used. However, in the subset of 14 families with ≥5 affected men per family, a 2.53-Mb shared consensus segment that overlaps with the previously published interval is identified. Combining these results with data from the earlier ICPCG study reduces the three-recombination interval at 22q12.3 to approximately 1.36 Mb. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

A locus for autosomal dominant accessory auricular anomaly maps to 14q11.2–q12

Accessory auricular anomaly is a small excrescence of skin that contains elastic cartilage on different regions of the helix and the face. Previous work has shown that the genetic trait of some patients with the isolated symptom of accessory auricular anomaly is autosomal dominant. To map the gene for autosomal dominant accessory auricular anomaly (ADAAA), we investigated a Chinese family with 11 affected individuals. We performed linkage analysis with microsatellite markers spanning the whole human-genome in the family. The inheritance pattern of the ADAAA family was autosomal dominant with complete penetrance. Two-point linkage analysis revealed significant maximum LOD scores of 4.20(D14S990 and D14S264, sita = 0) in the family. Haplotype construction and multipoint linkage analysis also confirmed the locus and defined the isolated ADAAA locus to a 9.84 cM interval between the markers D14S283 and D14S297. Our study assigned an isolated ADAAA locus to 14q11.2–q12. This is the first ADAAA locus reported to date.Y. Yang and J. Guo contribute to this work equally.     

The chromosomal localization of human β-galactosidase revisited: a locus for β-galactosidase on human chromosome 3 and for its protective protein on human chromosome 22

Summary A series of man-Chinese hamster and man-mouse somatic cell hybrids was investigated to study the localization of the genes coding for the human lysosomal enzyme -galactosidase (EC 3.2.1.23) and for its protective protein. Using a monoclonal antibody, raised against human placental -galactosidase, it was observed that the structural locus for the -galactosidase polypeptide is located on chromosome 3. The nature of the involvement of chromosome 22 in the expression of human -galactosidase was elucidated by metabolic labelling of the hybrids with radioactive amino acids, immunoprecipitation with monoclonal and polyclonal antibodies against -galactosidase, followed by analysis via gel electrophoresis and fluorography.The data show that the presence of chromosome 22 coincides with the presence of a 32 kd protein. This polypeptide, the protective protein was previously shown to be intimately associated with human -galactosidase. In addition, the protective protein was found to be essential for the in vivo stability of -galactosidase by aggregating -galactosidase monomers into high molecular weight multimes. Both chromosome 3 and 22 are therefore necessary to obtain normal levels og -galactosidase activity in human cells.     

Refinement of the hereditary neuralgic amyotrophy (HNA) locus to chromosome 17q24–q25

Hereditary neuralgic amyotrophy (HNA) is an autosomal dominant, recurrent focal neuropathy characterized by episodes of painful brachial plexus neuropathy with muscle weakness and atrophy, as well as sensory disturbances. Single episodes are commonly preceded by unspecific infections or immunization, or are associated with parturition. Minor facial dysmorphic features are present in some pedigrees but do not clearly segregate with the disease. To confirm the recently described HNA locus on distal chromosome 17q, we performed a genetic linkage study in an extended Turkish pedigree. We were able to refine the HNA locus on chromosome 17q24–q25 in a 16-cM region. Received: 21 October 1996     

Aicardi-Goutières syndrome displays genetic heterogeneity with one locus (AGS1) on chromosome 3p21

We have studied 23 children from 13 families with a clinical diagnosis of Aicardi-Goutières syndrome. Affected individuals had developed an early-onset progressive encephalopathy that was characterized by a normal head circumference at birth, basal ganglia calcification, negative viral studies, and abnormalities of cerebrospinal fluid comprising either raised white cell counts and/or raised levels of interferon-alpha. By means of genomewide linkage analysis, a maximum-heterogeneity LOD score of 5.28 was reached at marker D3S3563, with alpha=.48, where alpha is the proportion of families showing linkage. Our data suggest the existence of locus heterogeneity in Aicardi-Goutières syndrome and highlight potential difficulties in the differentiation of this condition from pseudo-TORCH (toxoplasmosis, rubella, cytomegalovirus, and herpes simplex virus types 1 and 2) syndrome.     

A gene responsible for Ghosal hemato-diaphyseal dysplasia maps to chromosome 7q33–34

Ghosal hemato-diaphyseal dysplasia is a rare autosomal recessive disorder characterized by a progressive sclerosing diaphyseal dysplasia and refractory anemia. The pathogenesis and genetic bases of this syndrome remain hitherto unknown. We have performed a genome wide search in two inbred families originating from Algeria and Tunisia. Here, we report on the mapping of a disease gene to chromosome 7q33–34 (Z _max = 4.21 at θ = 0 at locus D7S2513) in a 3.4 Mb defined by loci D7S2560 and AC091742. Ongoing studies will hopefully lead to identification of the disease-causing gene.     

A novel locus for autosomal dominant “uncomplicated” hereditary spastic paraplegia maps to chromosome 8p21.1-q13.3

Hereditary spastic paraplegias (HSPs) are genetically and phenotypically heterogeneous. Both “uncomplicated” and “complicated” forms have been described, with autosomal dominant, autosomal recessive, and X-linked inheritance. Hitherto, ten autosomal dominant “uncomplicated” HSP (ADHSP) loci have been mapped. Here, we report linkage of ADHSP with markers of the 8p21.1-q13.3 chromosomal region in a large French family, including 29 examined at-risk individuals. The age at onset varied from 8 to 60 years with a mean of 31.6 ± 16.4 years. Multipoint and two-point LOD-score calculations as well as haplotype reconstruction in this region gave support to the location of this novel ADHSP locus (SPG37) in a 43.5 cM genetic interval flanked by loci D8S1839 and D8S1795. The region was shared by all definitely (n = 13), probably (n = 3) and possibly (n = 2) affected patients with a maximum LOD score of 4.20 at the D8S601 locus. Two candidate genes, encoding the kinesin family member 13B and neuregulin 1 (isoforms SMDF and GFF2), were screened for mutations, but no disease-causing alterations were identified. Interestingly, another region, on chromosome 10q22.3-23.31, was found to segregate in all affected patients (but not in probably or possibly affected subjects) and in a high proportion of healthy at risk individuals, suggesting that this locus might act as a modifier of the phenotype. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Assignment of the gene for carboxypeptidase A to human chromosome 7q22→qter and to mouse chromosome 6

Summary A rat cDNA probe for preprocarboxypeptidase A was used to follow the segregation of the human gene for carboxypeptidase A (CPA) in 49 human x mouse somatic cell hybrids using Southern filter hybridization techniques. CPA was assigned to human chromosome 7q22qter. Similarly, the probe was used to follow the segregation of the mouse gene for carboxypeptidase A (Cpa) in 19 mouse x Chinese hamster somatic cell hybrids. Cpa was assigned to mouse chromosome 6. The gene for carboxypeptidase A forms part of a syntenic group that is conserved in man and mouse.Preliminary chromosomal assignments of carboxypeptidase A in man and mouse have been made in abstract (Honey et al. 1983a, b)