Locus heterogeneity in progressive familial intrahepatic cholestasis.

Progressive familial intrahepatic cholestasis (PFIC or Byler disease) is a rare autosomal recessive form of severe and fatal cholestatic liver disease. A locus for PFIC has recently been mapped to chromosome 18q21-q22 in the original Byler pedigree. This region harbours the locus for a related phenotype, benign recurrent intrahepatic cholestasis (BRIC), suggesting that these traits are allelic. Linkage analysis was undertaken in five consanguineous PFIC pedigrees from Saudi Arabia using marker loci (D18S69, D18S41, D18S64, D18S38, D18S42, D18S55, D18S68, and D18S61) which span the Byler disease/BRIC region on 18q21-q22. In this family set the disease locus was excluded from this region, showing that locus heterogeneity exists for the PFIC phenotype.     

Linkage of monogenic infantile hypertrophic pyloric stenosis to chromosome 16q24

Infantile hypertrophic pyloric stenosis (IHPS) is the most common inherited form of gastrointestinal obstruction in infancy. The disease is considered a paradigm for the sex-modified model of multifactorial inheritance and affects males four times more frequently than females. However, extended pedigrees consistent with autosomal dominant inheritance have been documented. We have analysed data from an extended IHPS family including eight affected individuals (five males and three females) and mapped the disease locus to chromosome 16q24 (LOD score=3.7) through an SNP-based genome wide scan. Fourteen additional multiplex pedigrees did not show evidence of linkage to this region, indicating locus heterogeneity.     

Mapping of a locus for progressive familial intrahepatic cholestasis (Byler disease) to 18q21-q22, the benign recurrent intrahepatic cholestasis region

A locus for progressive familial intrahepatic cholestasis (PFIC),also known as Byler disease, has been mapped to a 19 cM regionof chromosome 18 by a search for shared segments, using patientsfrom the Amish kindred in which the disorder was originallydescribed. A similar liver disease, benign recurrent intrahepaticcholestasis (BRIC), recently has been mapped to the same region,suggesting that these two diseases are caused by mutations inthe same gene. Although PFIC and BRIC are clinically distinctdiseases, episodic attacks of jaundice and pruritus, with elevatedconcentrations of bile acid in serum, are seen in both disorders.In PFIC patients, these attacks result in progressive liverdamage and death. The clinical and biochemical features of PFICand BRIC are suggestive of a defect in primary bile acid secretion.The biology of bile secretion is of great interest because ofits vital importance in digestion of dietary fats as well asin secretion of xenobiotics and metabolic waste products. Cloningof the gene (or genes) responsible for PFIC and BRIC will likelyprovide important insights into this pathway.     

Fifth finger camptodactyly maps to chromosome 3q11.2-q13.12 in a large German kindred

Camptodactyly (MIM 114200) is a digit deformity characterised by permanent flexion contracture of fifth fingers at the proximal interphalangeal (PIP) joints. The sporadic cases are common but a familial occurrence is not much appreciated. In an attempt to identify the genetic basis of camptodactyly, we have analysed a large German family with camptodactyly segregating in an autosomal dominant fashion. The affected family members exhibited clinical features of fifth finger camptodactyly and knuckle pads on the crooked fifth finger and on fingers 2-3. Typically, women were more severely affected than men. Microsatellite analyses of five candidate loci known to be associated with camptodactyly-like phenotypes did not show co-segregation with the phenotype in our family. A genome-wide linkage scan using a total of 414 microsatellite markers gave significant evidence of linkage between the familial phenotype and chromosomal locus 3q11.2-q13.12 (maximum two-point LOD score 3.04). The key recombination events showed that the phenotype localises between markers D3S2465 and D3S3044, spanning an interval of approximately 15 cM. This study reports the first genetic locus linked to isolated autosomal dominant fifth finger camptodactyly with knuckle pads and proves the hypothesis that camptodactyly is distinct from camptodactyly-associated phenotypes including Dupuytren contracture. Additional studies of other families will be necessary to determine the existence of genetic homogeneity or heterogeneity of the anomaly and to narrow down the genetic interval to identify the responsible gene. Since genetic heterogeneity for isolated camptodactyly is likely, we propose to designate the 3q11.2-q13.12 locus as CAMPD1 (ie, camptodactyly 1).     

Isolated autosomal dominant type E brachydactyly: exclusion of linkage to candidate regions 2q37 and 20q13.

Type E brachydactyly is a digital malformation which characteristically causes an asymmetrical shortening of one or more metacarpals or metatarsals or both. Although commonly seen as part of a syndrome, it can be inherited as an autosomal dominant characteristic, the gene acting with variable expressivity, but complete penetrance. As an Albright hereditary osteodystrophy (AHO)-like syndrome including brachydactyly type E and mental retardation may be caused by (micro) deletions at chromosome 2q37, this region together with the AHO locus at chromosome 20q13 were considered as candidate loci for brachydactyly type E. In this paper we described a family with isolated autosomal dominant type E brachydactyly in whom molecular analysis excludes linkage to these regions, providing support for further genetic heterogeneity of this trait.     

A newly identified locus for benign adult familial myoclonic epilepsy on chromosome 3q26.32-3q28

Benign Adult Familial Myoclonic Epilepsy (BAFME) is an autosomal dominant disorder characterized by adult-onset cortical tremor or action myoclonus predominantly in the upper limbs, and generalized seizures. We investigated a Thai BAFME family. Clinical and electrophysiological studies revealed that 13 were affected with BAFME. There were a total of 24 individuals studied. Genetic analysis by genome-wide linkage study (GWLS) was performed using 400 microsatellite markers and excluded linkage of the previous BAFME loci, 8q23.3-q24.1, and 2p11.1-q12.2. GWLS showed that the disease-associated region in our Thai family was linked to a newly identified locus on chromosome 3q26.32-3q28. This locus represents the fourth chromosomal region for BAFME.     

A novel locus for dHMN with pyramidal features maps to chromosome 4q34.3-q35.2

The distal hereditary motor neuropathy (dHMN) is a rare genetically and clinically heterogeneous disorder characterized by weakness and wasting of distal limb muscles in absence of overt sensory abnormalities. Recently, pyramidal signs have been also described in some patients with dominant or recessive dHMN, and two different loci have been identified in families affected by dHMN complicated with pyramidal dysfunction. We investigated an Italian family affected by an autosomal dominant dHMN complicated by pyramidal signs in order to map a new gene locus. The disease maps to a novel locus in a 26-cM region flanked by D4S1552 and D4S2930 on chromosome 4q34.3-35.2. Three candidate genes ( SNX25 , CASP3 and TUBB4Q ) located in the critical region were screened for the presence of mutations by heteroduplex analysis. No mutations have been detected in the analyzed genes. In conclusion, the new private genetic locus we reported further confirms the wide heterogeneity of dHMN.     

A novel chondroectodermal dysplasia mapped to chromosome 2q24.1-q31.1

Chondroectodermal dysplasias are genetically heterogeneous group of disorders involving defects in one or more ectodermal appendages (hair, nail, teeth and sweat glands) in association with anomalies of the cartilage. In the present study a novel form of chondroectodermal dysplasia, segregating in an autosomal recessive pattern in a Pakistani family, was investigated. The clinical features including proportionate short stature, osteopenia with fracturing and breaking of bones, hypodontia, hypertrophic and convex shaped nails, night blindness, watering eyes and infection of ears were observed in affected individuals of the family. Genetic linkage study mapped the novel autosomal recessive form of chondroectodermal dysplasia on human chromosome 2q24.1-q31.1. Linkage to the region was established by scanning human genome using Human Mapping 250K Nsp array. Linkage interval for chondroectodermal dysplasia on human chromosome 2q24.1-q31.1 spans 13.76 cM, which corresponds to 15.72 Mb according to the sequence-based physical map (Build 36.2). The maximum multipoint LOD score of 3.37 was obtained with several markers along the disease interval. Sequence analysis of three candidate genes (TANK, ITGB6, TBR1) located in the candidate interval did not discover potentially causal variants.     

Localisation of the gene causing diaphyseal dysplasia Camurati-Engelmann to chromosome 19q13

Camurati-Engelmann disease, progressive diaphyseal dysplasia, or diaphyseal dysplasia Camurati-Engelmann is a rare, autosomal dominantly inherited bone disease, characterised by progressive cortical expansion and sclerosis mainly affecting the diaphyses of the long bones associated with cranial hyperostosis. The main clinical features are severe pain in the legs, muscular weakness, and a waddling gait. The underlying cause of this condition remains unknown.In order to localise the disease causing gene, we performed a linkage study in a large Jewish-Iraqi family with 18 affected subjects in four generations. A genome wide search with highly polymorphic markers showed linkage with several markers at chromosome 19q13. A maximum lod score of 4.9 (theta=0) was obtained with markers D19S425 (58.7 cM, 19q13.1) and D19S900 (67.1 cM, 19q13. 2). The disease causing gene is located in a candidate region of approximately 32 cM, flanked by markers D19S868 (55.9 cM, 19q13.1) and D19S571 (87.7 cM, 19q13.4).     

Dyschromatosis universalis hereditaria: evidence for autosomal recessive inheritance and identification of a new locus on chromosome 12q21-q23

Dyschromatosis universalis hereditaria (DUH) and dyschromatosis symmetrica hereditaria (DSH) are pigmentary dermatoses most commonly seen in Japan. Both disorders usually show autosomal dominant inheritance, although in some cases autosomal recessive inheritance was reported. DSH was mapped to chromosome 1q21.3, and mutations in the gene ADAR ( DSRAD ) were identified in Japanese, Chinese and Taiwanese families with autosomal dominant DSH. A second locus for dyschromatosis was mapped on chromosome 6q24.2-q25.2 in two Chinese families initially reported to be affected with DSH, but later suggested to have autosomal dominant DUH. The aim of this study was to investigate whether one of these two loci is involved in the development of DUH in a consanguineous Bedouin family from Saudi Arabia with four affected and three unaffected sibs, clearly pointing to autosomal recessive inheritance. After excluding mutations in ADAR and linkage to the candidate regions on chromosomes 1 and 6, we performed an single nucleotide polymorphism-based genome-wide scan for linkage with other loci. Under the assumption of autosomal recessive inheritance, we have identified a new locus for dyschromatosis on chromosome 12q21-q23 in this Arab family with a maximum logarithm of the odds (LOD) score of 3.4, spanning a distance of 18.9 cM. Our study revealed the first locus for autosomal recessive DUH and supports recent evidence that DSH and DUH are genetically distinct disorders.     

Autosomal dominant retinitis pigmentosa locus on chromosome 19q in a Japanese family.

A large four generation Japanese family was studied, in which autosomal dominant retinitis pigmentosa (ADRP) of very variable expression was segregating. Positive lod scores with maxima between 1.557-5.118 at theta = 0.00, strongly suggestive of linkage, were obtained for KLK, D19S180, D19S418, and D19S254 on chromosome 19q. Recently, an ADRP locus has been mapped to the same region in a British family, in which, again, several members subjectively had no clinical evidence of the disease although they had both an affected parent and an affected child.     

Duplication 4q associated with chronic cholestatic changes in liver biopsy

We report a 15-day-old girl with partial trisomy 4q syndrome who presented with neonatal cholestasis. She had dysmorphic facial features and preaxial polysyndactyly of the right hand. The other findings were generalized hypertrichosis, pes equinovarus, oedema on feet and mild hepatomegaly. No specific reason for the cholestasis with elevated liver enzymes and direct bilirubinemia were characterized. Cytogenetic analyses revealed a karyotype 46,XX,der(13)t(4;13)(q25;p13). This is the first patient with partial trisomy 4q syndrome presented with neonatal cholestasis.     

Brazilian family with pure autosomal dominant spastic paraplegia maps to 8q: analysis of muscle beta 1 syntrophin

The autosomal dominant hereditary spastic paraplegias (AD-HSP) are a heterogeneous group of degenerative disorders of the central motor system, characterized by progressive spasticity of the lower limbs. Five loci for pure AD-HSP have been identified to date: SPG3 at 14q, SPG4 at 2p, SPG6 at 15q, SPG8 at 8q, and more recently SPG10 at 12q. We have analyzed a Brazilian family with 16 affected individuals by pure AD-HSP who developed progressive gait disturbance with onset at age 18-26 years. Linkage analysis performed with 13 relatives (6 affected and 7 normal) excluded SPG3, SPG4, and SPG6 as candidate regions. However, positive LOD scores were obtained with markers flanking the candidate region for the SPG8 locus [maximum two point Lod score (Zmax) = 3.3 at theta = 0 for D8S1804]. In this region lies the syntrophin beta 1 gene (SNT2B1), a widely expressed dystrophin-associated protein and therefore a good positional and functional candidate for this disease. Immunohistochemical and Western Blot (WB) studies showed that the distribution, expression, and apparent molecular weight of the beta 1 syntrophin protein were comparable to those of normal control individuals. Therefore, it is unlikely that defects in this protein are related to SPG8, at least in the present family.     

Linkage studies of bipolar disorder in the region of the Darier's disease gene on chromosome 12q23-24.1

We have recently described a family in which there is cosegregation of major affective disorder with Darier's disease and have mapped this autosomal dominant skin disorder to 12q23-q24.1. This has provided an interesting candidate region for genetic studies of bipolar disorder. We have studied the segregation of seven markers spanning the Darier's disease locus in 45 bipolar disorder pedigrees and found modest evidence in support of linkage under heterogeneity for 5 of these markers. Nonparametric analyses were suggestive of linkage with a marker at the gene encoding a secretory form of phospholipase A2. Our sample has relatively low power to detect linkage under heterogeneity and independent researchers should examine markers from this region in further samples of bipolar pedigrees. © 1995 Wiley-Liss, Inc.     

Mapping of a novel type III variant of Knobloch syndrome (KNO3) to chromosome 17q11.2

Knobloch syndrome (KNO) is an autosomal recessive disorder characterized by ocular abnormalities (myopia and retinal detachment) and occipital encephalocele. The syndrome is clinically and genetically heterogeneous (KNO1, KNO2). Previously germline mutations in COL18A1 (21q22.3) were detected in some families, but in other kindreds linkage to COL18A1 was excluded. We ascertained a large consanguineous family with high myopia, vitreoretinal degeneration and occipital scalp defect with autosomal recessive mode of inheritance. Due to the overlapping clinical presentation of this family with Knobloch syndrome we propose this phenotype as a type III variant of KS (KNO3). A genome wide linkage study using microsatellite markers at 10-20 cM interval revealed linkage to 17q11.2 with a maximum LOD scores 3.40 (theta = 0.00) for markers D17S1307 and D17S1166. Fine mapping defined a 2.67 cM disease region between D17S1307 and D17S798. Mutation analysis of three candidate genes (UNC119, MYO1D, and RAB11FIP4) within the disease region did not identify any disease-associated mutation in affected individuals.     

Oguchi disease: suggestion of linkage to markers on chromosome 2q.

Oguchi disease is a rare autosomal recessive form of congenital stationary night blindness. The condition is associated with fundus discolouration and abnormally slow dark adaptation. Earlier studies suggested that the 48 kD protein S antigen may be involved in the recovery phase of light transduction. Previous cytogenetic and linkage studies have localised the S antigen gene (SAG) to chromosome 2q37.1. In the present study markers which map to distal chromosome 2q were typed in an inbred Oguchi pedigree. The segregation data obtained suggested that the affected subjects are homozygous by descent for a region between D2S172 and D2S345. An intragenic SAG polymorphism was homozygous in all affected people and a recombination event suggested that SAG maps proximal to D2S345. Collectively, these findings support the hypothesis that a defect in S antigen may be responsible for Oguchi disease.     

Localization of a gene for Mobius syndrome to chromosome 3q by linkage analysis in a Dutch family

Mobius syndrome (MIM no. 157900) consists of a congenital paresis or paralysis of the VIIth cranial nerve, frequently accompanied by paralysis of other cranial nerves, orofacial and limb malformations, defects of the musculoskeletal system and mental retardation. Although most patients are sporadic cases, familial recurrence is not rare. Different pedigrees suggest different modes of inheritance. We performed linkage analysis in a large family with autosomal dominantly inherited Mobius syndrome, consisting essentially of asymmetric bilateral facial pareses. After exclusion of the candidate region for Mobius syndrome on 13q12.2-q13, we localized the gene to chromosome 3q21-22, indicating genetic heterogeneity of Mobius syndrome. This heterogeneity is further proven by the exclusion of both loci in a second family with Mobius syndrome.