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.     

Ataxia and pancytopenia caused by a mutation in TINF2

Disseminated superficial actinic porokeratosis (DSAP) is a chronic autosomal dominant cutaneous disorder with high genetic heterogeneity. Two genetic loci for DSAP were identified, but no specific genes were reported to date. The pathogenic mechanism of this disorder remains to be elucidated. In this study, a large, five-generation Chinese family with DSAP was genetically characterized. Two known DSAP loci, DSAP1 and DSAP2, two DSAP candidate genes (SART3 and SSH1), one DSP-linked locus and one PPPD-linked locus were first excluded in the family. The family was then characterized by genome-wide linkage analysis and a new DSAP locus was identified on chromosome 1p31.3–p31.1 with a maximum two-point LOD score of 5.09 with marker D1S2897 (θ = 0). Fine mapping showed that the disease gene was located within an 8.2 cM or 11.9 Mb region between markers D1S438 and D1S464. This is the third locus identified for DSAP (DSAP3). Eight candidate genes including GNG12, IL12RB2, ITGB3BP, DNAJ6, PIN1L, GADD45A, RPE65 and NEGR1 were sequenced, but found to be negative for functional sequence variants. Further mutational analysis of the candidate genes in the region will identify the specific gene for DSAP, which will provide insights into the pathogenesis of DSAP.     

A locus for autosomal dominant reflex epilepsy precipitated by hot water maps at chromosome 10q21.3-q22.3

Hot water epilepsy (HWE) is a form of reflex or sensory epilepsy wherein seizures are precipitated by an unusual stimulus, the contact of hot water over the head and body. Genome-wide linkage analysis of a large family with ten affected members, provided evidence of linkage (Z _max = 3.17 at θ = 0 for D10S412) to chromosome 10q21. Analysis of five additional HWE families, for markers on chromosome 10, further strengthened the evidence of linkage to the same chromosomal region with three out of five families showing concordance for the disease haplotype and providing a two-point LOD score of 4.86 at θ = 0 and 60% penetrance for D10S412. The centromere-proximal and -distal boundaries of the critical genetic interval of about 15 Mb at 10q21.3-q22.3 were defined by D10S581 and D10S201, respectively. Sequence analysis of a group of functional candidate genes, the ion channels KCNMA1, VDAC2 and solute carriers SLC25A16, SLC29A3 revealed no potentially pathogenic mutation. We propose to carry out further analysis of positional candidate genes from this region to identify the gene responsible for this unusual neurobehavioral phenotype.     

Genome-wide linkage of febrile seizures and epilepsy to the FEB4 locus at 5q14.3-q23.1 and no MASS1 mutation

Febrile seizures (FS) represent the most common seizure disorder in childhood and contribution of a genetic predisposition has been clearly proven. In some families FS is associated with a wide variety of afebrile seizures. Generalized epilepsy with febrile seizures plus (GEFS+) is a familial epilepsy syndrome with a spectrum of phenotypes including FS, atypical febrile seizures (FS+) and afebrile generalized and partial seizures. Mutations in the genes SCN1B, SCN1A and GABRG2 were identified in GEFS+ families. GEFS+ is genetically heterogeneous and mutations in these three genes were detected in only a minority of the families. We performed a 10 cM density genome-wide scan in a multigenerational family with febrile seizures and epilepsy and obtained a maximal multipoint LOD score of 3.12 with markers on chromosome 5q14.3-q23.1. Fine mapping and segregation analysis defined a genetic interval of ≈33 cM between D5S2103 and D5S1975. This candidate region overlapped with a previously reported locus for febrile seizures (FEB4) in the Japanese population, in which MASS1 was proposed as disease gene. Mutation analysis of the exons and exon–intron boundaries of MASS1 in our family did not reveal a disease causing mutation. Our linkage data confirm for the first time that a locus on chromosome 5q14-q23 plays a role in idiopathic epilepsies. However, our mutation data is negative and do not support a role for MASS1 suggesting that another gene within or near the FEB4 locus might exist.     

A novel genetic locus for familial febrile seizures and epilepsy on chromosome 3q26.2–q26.33

Febrile seizures (FS) are common in children, and the incidence is 2–5% before the age of 5 years. A four-generation Chinese family with autosomal dominant febrile seizure and epilepsy was studied by genome-wide linkage analysis. Significant linkage was identified with markers on chromosome 3q26.2–26.33 with a maximum pairwise LOD score of >3.00. Fine mapping defined the new genetic locus within a 10.7-Mb region between markers D3S3656 and D3S1232. A maximum multipoint LOD score of 5.27 was detected at marker D3S1565. A previously reported CLCN2 gene for epilepsy was excluded as the disease-causing gene in the family by mutational analysis of all exons and exon–intron boundaries of CLCN2 and by haplotype analysis. Mutation analysis of KCNMB2 and KCNMB3, which were two potassium-channel genes in this linkage region, did not reveal a disease causing mutation. Our results identified another novel locus on chromosome 3q26.2–26.33, and future studies of the candidate genes at the locus will identify a new gene for combined FS and idiopathic epilepsies. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users. X.-H. Dai, W.-W. Chen, and X. Wang contributed equally to this work.     

A genome-wide scan for loci linked to forearm bone mineral density

Osteoporosis is a chronic disorder characterized by low bone mass and fragility fractures. It affects more than 25 million men and women in the United States alone. Although several candidate genes, such as the vitamin-D-receptor gene or the estrogen-receptor gene, have been suggested in the pathogenesis of osteoporosis, the genetic dissection of this disorder remains a daunting task. To search systematically for chromosomal regions containing genes that regulate bone mineral density (BMD), we scanned the entire autosomal genome by using 367 polymorphic markers among 218 individuals (153 sibpairs) from 96 nuclear families collected from three townships of Anqing, China. In these 96 families, DNA samples from both parents were available for 82 (85.4%) families. By using age- and gender-adjusted forearm BMD measurements, a peak on chromosome 2 near D2S2141, D2S1400, and D2S405, a region previously linked to spinal BMD, showed evidence of linkage to both proximal and distal forearm BMD (multipoint LOD=2.15 and 2.14 for proximal and distal forearm BMD, respectively). One region on chromosome 13 (multipoint LOD=1.67) in the proximity of D13S788 and D13S800 showed evidence of linkage to distal forearm BMD only. Possible candidate genes included CALM2 (calmodulin 2) at 2p21.3-p21.1, a putative STK (serine/threonine kinase) at 2p23–24, POMC (pro-opiomelanocortin) at 2p23.3, and COL4A1 and COL4A2 (collagen IV alpha-1 and alpha-2 subunits) at 13q34. Because of the limited sample size, the suggestive evidence of linkage of this study should be considered as tentative and needs to be replicated in other larger populations. Received: 19 November 1998 / Accepted: 22 January 1999     

A homozygous mutation in LTBP2 causes isolated microspherophakia

Microspherophakia is an autosomal-recessive congenital disorder characterized by small spherical lens. It may be isolated or occur as part of a hereditary systemic disorder, such as Marfan syndrome, autosomal dominant and recessive forms of Weill-Marchesani syndrome, autosomal dominant glaucoma–lens ectopia–microspherophakia–stiffness–shortness syndrome, autosomal dominant microspherophakia with hernia, and microspherophakia-metaphyseal dysplasia. The purpose of this study was to map and identify the gene for isolated microspherophakia in two consanguineous Indian families. Using a whole-genome linkage scan in one family, we identified a likely locus for microspherophakia (MSP1) on chromosome 14q24.1–q32.12 between markers D14S588 and D14S1050 in a physical distance of 22.76 Mb. The maximum multi-point lod score was 2.91 between markers D14S1020 and D14S606. The MSP1 candidate region harbors 110 reference genes. DNA sequence analysis of one of the genes, LTBP2, detected a homozygous duplication (insertion) mutation, c.5446dupC, in the last exon (exon 36) in affected family members. This homozygous mutation is predicted to elongate the LTBP2 protein by replacing the last 6 amino acids with 27 novel amino acids. Microspherophakia in the second family did not map to this locus, suggesting genetic heterogeneity. The present study suggests a role for LTBP2 in the structural stability of ciliary zonules, and growth and development of lens.     

Hereditary neuralgic amyotrophy: evidence for genetic homogeneity and mapping to chromosome 17q25

Hereditary neuralgic amyotrophy (HNA) is a rare autosomal dominant disorder on chromosome 17q, associated with recurrent, episodic, painful brachial plexus neuropathy. Dysmorphic features, including hypotelorism, long nasal bridge and facial asymmetry, are frequently associated with HNA. To assess genetic homogeneity, determine the cytogenetic location, and identify flanking markers for the HNA locus, six pedigrees were studied with multiple DNA markers from distal chromosome 17q. The results in all pedigrees supported linkage of the HNA locus to chromosome 17. A maximum combined lod score (Ζ = 10.94, ￡ = 0.05) was obtained with marker D17S939 and the maximum multipoint lod score was 22.768 in the interval defined by D17S802– D17S939. An analysis of crossovers placed the HNA locus within an approximate 4.0-cM interval flanked by D17S1603 and D17S802. Analysis of DNA from a human/mouse somatic cell hybrid with linked markers suggests that band 17q25 harbors the HNA locus. These results support genetic homogeneity within HNA and define a specific interval and a precise cytogenetic location in chromosome 17q25 for this disorder. Received: 24 June 1997 / Accepted: 21 August 1997     

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.     

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.     

A new locus for autosomal dominant Charcot-Marie-Tooth disease type 2 (CMT2L) maps to chromosome 12q24

Charcot-Marie-Tooth disease (CMT) is one of the most common inherited neurological disorders with a prevalence estimated at 1/2500. The axonal form of this disorder is referred to as Charcot-Marie-Tooth type 2 disease (CMT2). Recently, a large Chinese family with CMT2 was found in the Hunan and Hubei provinces of China. The known loci for CMT1A, CMT2D, CMT1B (the same locus is also responsible for CMT2I and CMT2J), CMT2A, CMT2E, and CMT2F were excluded in this family by linkage analysis. A genome-wide screening was then carried out, and the results revealed linkage of CMT2 to a locus at chromosome 12q24. Haplotype construction and analyses localized this novel locus to a 6.8-cM interval between microsatellite markers D12S366 and D12S1611. The maximal two-point LOD score of 6.35 and multipoint LOD score of 8.08 for marker D12S76 at a recombination fraction () of 0 strongly supported linkage to this locus. Thus, CMT2 neuropathy in this family represents a novel genetic entity that we have designated as CMT2L.     

Assignment of linkage groups to pea chromosomes after karyotyping and gene mapping by fluorescent in situ hybridization

Chromosomes of the pea (Pisum sativum L.) were submitted to fluorescent in situ hybridization (FISH) with probes specific for the oligonucleotides (AG)₁₂, (AC)₁₂, (GAA)₁₀, and (GATA)₇ and for the genes encoding 25S rRNA, 5S rRNA and the storage proteins legumin A, K and vicilin. A fourth 5S rRNA gene locus, apparently specific for an accession of the cultivar Grüne Victoria, was newly detected. This allowed all seven chromosome pairs to be distinguished by FISH signals of rRNA genes. The same was possible using a combination of oligonucleotide probes or of oligonucleotides and rRNA gene-specific probes in multicolour FISH. Rehybridization with the 5S rRNA gene-specific probe allowed us to assign vicilin genes to the short arm of chromosome 5, the single legumin A locus to the long arm of chromosome 3 and the legumin B-type genes (exemplified by legumin K) to one locus on the short arm of chromosome 6. Correlation of these data with an updated version of the pea genetic map allowed the assignment of most linkage groups to defined chromosomes. It only remains to be established which of linkage groups IV and VII corresponds to the satellited chromosomes 4 or 7, respectively. Received: 13 February 1998; in revised form: 3 April 1998 / Accepted: 7 April 1998     

Mutations in STIL, Encoding a Pericentriolar and Centrosomal Protein, Cause Primary Microcephaly

Primary microcephaly (MCPH) is an autosomal-recessive congenital disorder characterized by smaller-than-normal brain size and mental retardation. MCPH is genetically heterogeneous with six known loci: MCPH1–MCPH6. We report mapping of a novel locus, MCPH7, to chromosome 1p32.3–p33 between markers D1S2797 and D1S417, corresponding to a physical distance of 8.39 Mb. Heterogeneity analysis of 24 families previously excluded from linkage to the six known MCPH loci suggested linkage of five families (20.83%) to the MCPH7 locus. In addition, four families were excluded from linkage to the MCPH7 locus as well as all of the six previously known loci, whereas the remaining 15 families could not be conclusively excluded or included. The combined maximum two-point LOD score for the linked families was 5.96 at marker D1S386 at θ = 0.0. The combined multipoint LOD score was 6.97 between markers D1S2797 and D1S417. Previously, mutations in four genes, MCPH1, CDK5RAP2, ASPM, and CENPJ, that code for centrosomal proteins have been shown to cause this disorder. Three different homozygous mutations in STIL, which codes for a pericentriolar and centrosomal protein, were identified in patients from three of the five families linked to the MCPH7 locus; all are predicted to truncate the STIL protein. Further, another recently ascertained family was homozygous for the same mutation as one of the original families. There was no evidence for a common haplotype. These results suggest that the centrosome and its associated structures are important in the control of neurogenesis in the developing human brain.     

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 Leber congenital amaurosis on chromosome 14q24

Leber congenital amaurosis (LCA) is a clinically and genetically heterogeneous autosomal recessive retinal dystrophy and the most common genetic cause of congenital visual impairment. We used a DNA pooling strategy comparing the genotypes of affected to unaffected control pools in a genome-wide search for identity-by-descent on a consanguineous Saudi Arabian LCA family. A shift to homozygosity was observed in the affected DNA pool compared with the control pool at linked markers D14S606 and D14S610. Genotyping of individual DNA samples from the entire pedigree for marker D14S74, closely linked to these loci, and several flanking markers confirmed linkage with a Z_MAX=13.29 at θ=0.0. These data assign a third locus (LCA3) for LCA to chromosome 14q24. This locus and the previously identified loci are excluded for other Saudi Arabian pedigrees, both confirming that this clinical disorder is genetically heterogeneous and that additional LCA genes remain to be identified. Received: 5 February 1998 / Accepted: 2 June 1998     

Genetic fine localization of the β-glucocerebrosidase (GBA) and prosaposin (PSAP) genes: implications for Gaucher disease

Mutations in the glucocerebrosidase (GBA) and prosaposin (PSAP) genes are responsible for Gaucher disease, the most prevalent sphingolipidosis. Somatic cell hybrid analysis and in situ hybridization experiments have localized the GBA gene to 1q21 and the PSAP gene to 10q21-q22. We performed pairwise and multi-point linkage analyses between the two genes and several highly polymorphic markers from the Généthon human linkage map. Our results show that six markers cosegregate with the GBA gene (Z_max = 8.73 at θ = 0.00 for marker D1S2714) and define a 3.2-cM interval between D1S305 and D1S2624 as the most probable location for the gene. Three of these markers (D1S2777, D1S303, and D1S2140), as well as the gene encoding pyruvate kinase (PKLR), are contained in a single YAC clone together with the GBA gene. A new polymorphism was identified within the PSAP gene (C16045T) and used for linkage studies. The multi-point analysis places the gene in a 9.8-cM interval between D10S1688 and D10S607. The fine localization of these genes provides a useful tool for cosegregation analysis, indirect molecular diagnosis, and population genetic studies. Received: 22 October 1996 / Accepted: 4 February 1997     

Genetic mapping of hph2, a mutation affecting amino acid transport in the mouse

We describe the genetic mapping of hyperphenylalaninemia 2 (hph2), a recessive mutation in the mouse that causes deficient amino acid transport similar to Hartnup Disorder, a human genetic amino acid transport disorder. The hph2 locus was mapped in three separate crosses to identify candidate genes for hph2 and a region of homology in the human genome where we propose the Hartnup Disorder gene might lie. The mutation maps to mouse Chromosome (Chr) 7 distal of the simple sequence length polymorphism (SSLP) marker D7Mit140 and does not recombine with D7Nds4, an SSLP marker in the fibroblast growth factor 3 (Fgf3) gene. Unexpectedly, the mutant chromosome affects recombination frequency in the D7Mit12 to D7Nds4 interval. Received: 16 May 1996 / Accepted: 25 September 1996     

A gene locus for progressive familial heart block type II (PFHBII) maps to chromosome 1q32.2-q32.3

Cardiac conduction defects that are associated with dilated cardiomyopathy (DCM) are generally considered to be sporadic clinical entities, although familial forms of disorders with these clinical features have been identified in a number of families in different countries. An autosomal dominant cardiac disorder characterised by conduction abnormalities and DCM, termed progressive familial heart block type II (PFHBII) (OMIM 140400), has been described in a South African Caucasian family of Northern European descent. Known candidate loci for isolated conduction disorders, isolated DCM and conduction disorders complicated by DCM were excluded from disease causation in this family by linkage analysis, with the exception of the DCM-associated (CMD1D) locus on chromosome 1q32, where a maximum multipoint lod score of 3.7 in the interval between D1S3753 and D1S414, was generated. This region encompassed the troponin T gene (TNNT2), however, genetic fine mapping and haplotype analysis excluded TNNT2 as cause of PFHBII and placed the disease-causative gene within a 3.9 cM (2.85 Mb) interval, flanked by D1S70 and D1S505. Analysis of KCNH1, KIAA0205, LAMB3 and PPP2R5A, which map within the critical interval, indicated that the PFHBII-causative mutation does not lie within the coding regions or splice junctions of these plausible candidate genes. The data indicate the existence of a novel locus involved in the pathogenesis of cardiac conduction abnormalities and DCM.     

A novel locus for maternally inherited human gingival fibromatosis at chromosome 11p15

Human isolated gingival fibromatosis is an oral disorder characterized by a slowly progressive benign enlargement of gingival tissues. The most common genetic form, hereditary gingival fibromatosis (HGF), is usually transmitted as an autosomal dominant trait. We report here for the first time a newly identified maternally inherited gingival fibromatosis in two unrelated Chinese families and mapped this disease locus to human chromosome 11p15 with a maximum two point LOD score of 8.70 at D11S4046 (θ = 0) for family 1 and of 6.02 at D11S1318 for family 2. Haplotype analysis placed the critical region in the interval defined by D11S1984 and D11S1338. A cluster of maternally expressed genes is within this critical region. We screened individuals in these two families for mutations for all known maternally expressed genes within this region. None was found either within the coding sequence or at the intron–exon boundary of these genes. Neither did we detect any loss of imprinting in three informative imprinted genes including H19, KCNQ1 downstream neighbor (KCNQ1DN) and cyclin-dependent kinase inhibitor 1C (CDKN1C). However, gene expression profile analysis revealed reduced expression of hemoglobin beta (HBB), hemoglobin delta (HBD), hemoglobin gamma A (HBG1) and hemoglobin gamma G (HBG2) genes at disease locus in HGF patients. This study suggests that genome imprinting might affect the development of HGF. Electronic supplementary material Supplementary material is available in the online version of this article at and is accessible for authorized users. Conflict Of Interest Statement: No competing financial interests.