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A family has been identified in which 13 of the 31 family members examined have hereditary motor and sensory neuropathy (HMSN), an inherited disorder of the peripheral nerves. What makes this family different, however, is that 8 of the 13 affected family members also have unmistakable signs of myotonic dystrophy (MyD). The majority of family pedigrees of HMSN show signs of linkage to chromosome 17. The disorder is heterogeneous, however, and some families with similar symptoms show linkage of their disorder to the Duffy blood group locus on chromosome 1. However, the gene for myotonic dystrophy is on chromosome 19, extremely close to the gene for apolipoprotein C2. Investigation of this family revealed no signs that the inherited disorder was located on chromosome 17. Using DNA markers for the apolipoprotein C2 gene, it was found that all affected individuals inherited a unique form of the gene which could not be found in the unaffected members of the family. This strongly suggests that the genetic disorder in this family is closely linked to the apolipoprotein C2 gene, and is located on chromosome 19. Since HMSN is heterogeneous, it is possible that there exists an HMSN gene which is closely linked to the MyD gene, and that eight of the family members in the present kinship have inherited both genes. However, a more plausible explanation is that some mutations of the MyD gene may result in symptoms of HMSN. It is known that different family groups with HMSN often have different clinical forms of the disease. The authors speculate that an unusual mutation in this family causes symptoms of HMSN, and in a few individuals results in the symptoms associated with MyD, as well. (Consumer Summary produced by Reliance Medical Information, Inc.)

Genetic and metabolic studies have been done on a large kindred in which several males are affected by a syndrome of borderline mental retardation and abnormal behavior. The types of behavior that occurred include impulsive aggression, arson, attempted rape, and exhibitionism. Analysis of 24-hour urine samples indicated markedly disturbed monoamine metabolism. This syndrome was associated with a complete and selective deficiency of enzymatic activity of monoamine oxidase A (MAOA). In each of five affected males, a point mutation was identified in the eighth exon of the MAOA structural gene, which changes a glutamine to a termination codon. Thus, isolated complete MAOA deficiency in this family is associated with a recognizable behavioral phenotype that includes disturbed regulation of impulsive aggression., Studies of aggressive behavior in animals and humans have implicated altered metabolism of serotonin[1-7], and to a lesser extent dopamine[4,8,9], and noradrenaline[3-5, 10-12]. These observations suggest that genetic defects in [...]

Robinow Syndrome ( RS), a rare skeletal dysplasia syndrome, is characterized by dysmorphic features resembling a fetal face, mesomelic limb shortening, hypoplastic external genitalia in males, and renal and vertebral anomalies. Both autosomal dominant and autosomal recessive patterns of inheritance have been reported. Since the description of autosomal dominant Robinow Syndrome ( ADRS; OMIM 180700) in 1969 by Meinhard Robinow and colleagues, the molecular etiology remained elusive until only recently. WNT5A was proposed to be the candidate gene for ADRS, as mutations were found in two affected families, one of those being the originally described index family. We report three families with RS caused by novel heterozygous WNT5A mutations, which were confirmed in the first family by whole exome sequencing, and in all by Sanger sequencing. To our knowledge, this is the largest number of published families with ADRS in whom a WNT5A mutation was identified. Families 1 and 2 are the first cases showing de novo inheritance in the affected family members and thus strengthen the evidence for WNT5A as the causative gene in ADRS. Finally, we propose WNT5A mutation specificity in ADRS, which may affect interactions with other proteins in the Wnt pathway. [ABSTRACT FROM AUTHOR]

van Reeuwijk J, Brunner HG, van Bokhoven H. Glyc-O-genetics of Walker–Warburg syndrome.Walker–Warburg syndrome (WWS) is the most severe of a group of multiple congenital anomaly disorders known as the cobblestone lissencephalies. These are characterized by congenital muscular dystrophy in conjunction with severe brain malformation and ocular abnormalities. In the last 3 years, important progress has been made towards the elucidation of the genetic causes of these disorders. Mutations in three genes,POMT1,fukutinandFKRP, have been described for WWS, which together account for approximately 20% of patients with Walker–Warburg. It has become evident that some of the underlying genes may cause a broad spectrum of phenotypes, ranging from limb girdle muscular dystrophy type 2I to WWS. In some cases, a genotype–phenotype correlation can be recognized. In line with the known or proposed functions of the resolved genes, all patients with cobblestone lissencephaly show defects in the O-linked glycosylation of the glycoproteinα-dystroglycan. Perhaps, the missing genes underlying the remainder of the unexplained WWS patients have also to be sought in the pathways involved in O-linked protein glycosylation. [ABSTRACT FROM AUTHOR]

Explains that medical genetics researchers have constructed, validated, and applied a full coverage chromosome X BAC array for array based comparative genomic hybridization array. 25 percent of mental retardation in males is due to genetic defect linked to X chromosome; High resolution copy number screening in the search for MRX genes.

Discusses the development of a Walker-Warburg syndrome phenotype through a homozygous nonsense mutation in the Fukutin gene. Development of the cerebral cortex through neural migration; Proliferation of sets of neurons at the subventricular zone; Response of neurons to the stop signals at the cobblestone neocortex.

Investigates the ophthalmological characteristics and molecular cause of retinal dystrophy in patients from families from a genetic isolate in Netherlands. Involvement of RPE65 gene; Identification of heterozygous carriers; Risk of blindness in offspring of patients, their heterozygous siblings and other heterozygous individuals of the genetic isolate.

The thrombocytopenia-absent radius (TAR) syndrome is a congenital malformation syndrome characterised by bilateral absence of the radii and a thrombocytopenia. The lower limbs, gastrointestinal, cardiovascular, and other systems may also be involved. Shaw and Oliver in 1959 were the first to describe this condition, but it was Hall et al in 1969 who reported the first major series of patients. Since then most reports have been based on single or small numbers of cases. We report the results of a clinical study looking at the phenotype of 34 patients with TAR syndrome. All cases had a documented thrombocytopenia and bilateral radial aplasia, 47% had lower limb anomalies, 47% cow's milk intolerance, 23% renal anomalies, and 15% cardiac anomalies. Congenital anomalies not previously described in association with TAR syndrome included facial capillary haemangiomata, intracranial vascular malformation, sensorineural hearing toss, and scoliosis. Karyotype analysis, chromosome breakage studies including premature centromeric separation and fluorescence in situ hybridisation studies looking for a deletion of chromosome 22q11 were undertaken. Two abnormal karyotypes were identified. [ABSTRACT FROM AUTHOR]

We report 18 patients with cutis marmorata telangiectatica congenita (CMTC) who visited the University Hospital Nijmegen between 1982 and 1999. In 11 patients (61%), associated abnormalities of varying severity were observed. Three of these patients had a previously described distinct syndrome comprising CMTC, a naevus flammeus at the upper lip/philtrum, macrocephaly and syndactyly, among other abnormalities. Findings in the other eight patients with associated abnormalities included hydrocephalus, hyperplasia/hypoplasia (body asymmetry), anal atresia, hearing loss, cardiovascular abnormalities, strabismus hypothyroidism, haemangioma, naevus anaemicus, café-au-lait spot, lipoma and an elevation of the right diaphragm. All cases were sporadic. [ABSTRACT FROM AUTHOR]

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 θ=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. © 2005 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Presents a correction of the error made in the article on the mutation of the deoxyguanosin kinase gene.

Abstract: Purpose: To assess the occurrence of high-risk epithelial lesions in women of breast cancer families with and without a BRCA mutation. Patients and methods: Prospective study of women at very high risk of breast cancer undergoing prophylactic mastectomy (68 BRCA1 mutation carriers, 14 BRCA2 mutation carriers and 24 non-BRCA mutation carriers). Results: The prevalence of high-risk lesions is equal in women with a BRCA1 or a BRCA2 mutation, but is higher in non-BRCA mutation carriers: all lesions 43% versus 71% (p =0.02), atypical lobular hyperplasia 26% versus 67% (p =0.001), atypical ductal hyperplasia 17% versus 42% (p =0.01), lobular carcinoma-in situ 15% versus 29% (p =0.10) and ductal carcinoma-in situ 9% versus 17% (p =0.25). The presence of high-risk lesions is related to absence of a BRCA mutation and to age over 40 years. Conclusion: Women with an autosomal dominant family history for breast cancer, with and without a BRCA mutation are prone to develop high-risk epithelial lesions, especially over 40 years. [Copyright &y& Elsevier]

To identify novel genes that are expressed specifically or preferentially in the cochlea, we constructed a cDNA library enriched for human cochlear cDNAs using a suppression subtractive hybridization technique. We analyzed 2640 clones by sequencing and BLAST similarity searches. One hundred and fifty-five different cDNA fragments mapped in nonsyndromic hearing impairment loci for which the causative gene has not been cloned yet. Approximately 30% of the clones show no similarity to any known human gene or expressed sequence tag (EST). Clones mapping in nonsyndromic deafness loci and a selection of clones that represent novel ESTs were analyzed by reverse transcriptase-polymerase chain reaction (RT-PCR) of RNA derived from 12 human fetal tissues. Our data suggest that a quarter of the novel genes in our library are preferentially expressed in fetal cochlea. These may play a physiologically important role in the hearing process and represent candidate genes for hereditary hearing impairment. [Copyright &y& Elsevier]

Background: Carriers of Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) may show muscle weakness or dilated cardiomyopathy. Studies focusing on skeletal-muscle involvement were done before DNA analysis was possible. We undertook a cross-sectional study in a population of definite carriers to estimate the proportion and to assess the clinical profile of carriers with symptoms. We also assessed a possible correlation between genotype and phenotype.Methods: Carriers of DMD and BMD, aged 18-60 years, were traced through the files of the central register kept at the Department of Human Genetics in Leiden, Netherlands. For each carrier who agreed to participate a medical history was taken, and muscle-strength assessment by hand-held dynamometry and manual muscle testing and cardiological assessment were done.Findings: 129 carriers of muscular dystrophy (85 DMD, 44 BMD) participated in the study. In 90 women from 52 (70%) families, 37 different mutations were found. 28 (22%) women had symptoms. 22 (17%) had muscle weakness, varying from mild to moderately severe. Muscle weakness was found in carriers of DMD and BMD, but dilated cardiomyopathy was found only in seven (8%) carriers of DMD, of whom one had concomitant muscle weakness. There was an unexpectedly high proportion of left-ventricle dilation (18%). No genotype-phenotype correlation was found.Interpretation: Clinical manifestation of muscle weakness, dilated cardiomyopathy, or both can be found in about a fifth of carriers of DMD and BMD. If left-ventricle dilation is taken into account, the proportion of carriers with symptoms is even higher, amounting to 40%. [ABSTRACT FROM AUTHOR]