Localisation of a gene implicated in a severe speech and language disorder.

Between 2 and 5% of children who are otherwise unimpaired have significant difficulties in acquiring expressive and/or receptive language, despite adequate intelligence and opportunity. While twin studies indicate a significant role for genetic factors in developmental disorders of speech and language, the majority of families segregating such disorders show complex patterns of inheritance, and are thus not amenable for conventional linkage analysis. A rare exception is the KE family, a large three-generation pedigree in which approximately half of the members are affected with a severe speech and language disorder which appears to be transmitted as an autosomal dominant monogenic trait. This family has been widely publicised as suffering primarily from a defect in the use of grammatical suffixation rules, thus supposedly supporting the existence of genes specific to grammar. The phenotype, however, is broader in nature, with virtually every aspect of grammar and of language affected. In addition, affected members have a severe orofacial dyspraxia, and their speech is largely incomprehensible to the naive listener. We initiated a genome-wide search for linkage in the KE family and have identified a region on chromosome 7 which co-segregates with the speech and language disorder (maximum lod score = 6.62 at theta = 0.0), confirming autosomal dominant inheritance with full penetrance. Further analysis of microsatellites from within the region enabled us to fine map the locus responsible (designated SPCH1) to a 5.6-cM interval in 7q31, thus providing an important step towards its identification. Isolation of SPCH1 may offer the first insight into the molecular genetics of the developmental process that culminates in speech and language.

Association of the INS VNTR with size at birth. ALSPAC Study Team. Avon Longitudinal Study of Pregnancy and Childhood.

Size at birth is an important determinant of perinatal survival and has also been associated with the risk for cardiovascular disease and type 2 diabetes in adult life. Common genetic variation that regulates fetal growth could therefore influence perinatal survival and predispose to the development of adult disease. We have tested the insulin gene (INS) variable number of tandem repeats (VNTR) locus, which in Caucasians has two main allele sizes (class I and class III; ref. 3), as a functional candidate polymorphism for association with size at birth, as it has been shown to influence transcription of INS (refs 3-5). In a cohort of 758 term singletons (Avon Longitudinal Study of Pregnancy and Childhood; ALSPAC) followed longitudinally from birth to 2 years, we detected significant genetic associations with size at birth: class III homozygotes had larger mean head circumference (P=0.004) than class I homozygotes. These associations were amplified in babies who did not show postnatal realignment of growth (45%), and were also evident for length (P=0.015) and weight (P=0.009) at birth. The INS VNTR III/II genotype might have bestowed a perinatal survival during human history by conferring larger size at birth. Common genetic variation of this kind may contribute to reported associations between birth size and adult disease.

F-cell production in sickle cell anemia: regulation by genes linked to beta-hemoglobin locus.

Strong correlation of F-reticulocyte levels within sib pairs with sickle cell (SS) anemia suggests that the wide-ranging levels found in the SS population are governed by genes linked to the beta S-site. Correlations between F-cell levels in parents and F-reticulocyte levels in their children indicates that these same genes regulate F-cell production in nonanemic persons. Comparison of outcrossed and inbred SS populations suggests that relative well-being arises from homozygosity for alleles dictating high F-reticulocyte response to anemia.

Association between X-linked mixed deafness and mutations in the POU domain gene POU3F4.

Deafness with fixation of the stapes (DFN3) is the most frequent X-linked form of hearing impairment. The underlying gene has been localized to a 500-kilobase segment of the Xq21 band. Here, it is reported that a candidate gene for this disorder, Brain 4 (POU3F4), which encodes a transcription factor with a POU domain, maps to the same interval. In five unrelated patients with DFN3 but not in 50 normal controls, small mutations were found that result in truncation of the predicted protein or in nonconservative amino acid substitutions. These findings indicate that POU3F4 mutations are a molecular cause of DFN3.

Mapping and cloning hereditary deafness genes.

In the past two years, considerable progress has been made in the mapping and cloning of human deafness genes. Highlights are the chromosomal localization of at least five genes for autosomal forms of non-syndromic deafness and, more recently, the cloning of an X-linked deafness gene, DFN3, and the Usher syndrome type IB gene. This last gene encodes a myosin-like protein and was identified as the human homolog of the mouse shaker-1 gene. The DFN3 gene Brain 4 encodes a POU domain containing transcription factor that is involved in the development of the inner ear.

A premutation that generates a defect at crossing over explains the inheritance of fragile X mental retardation.

The view that the Martin-Bell syndrome (X-linked mental retardation with fragile site at Xq27/8) is inherited in a regular X-linked fashion is becoming untenable with the increasing number of reports of transmission through phenotypically normal males. Analysis of the published pedigrees containing such males shows that their heterozygous daughters are never mentally retarded, and have either no fragile site or very few indeed. By contrast, in the next generation, a third of the female heterozygotes are mentally subnormal with an average of 29% fragile sites. These data suggest a premutation that generates the definitive mutation only when transmitted by a female. We propose an inherited sub-microscopic chromosome rearrangement involving the Xq27/8 region that causes no ill effect per se, but generates a significant genetic imbalance when involved in a recombination event with the other X chromosome. This hypothesis explains many of the puzzling genetic aspects of the Martin-Bell syndrome, but it also complicates the interpretation of linkage analysis with genetic markers.

Difference in methylation patterns within the D15S9 region of chromosome 15q11-13 in first cousins with Angelman syndrome and Prader-Willi syndrome.

Abnormalities of chromosome region 15q11-13 are associated with Angelman syndrome (AS) and Prader-Willi syndrome (PWS). Differences between the methylation patterns of the region of chromosome 15q11-13 which hybridizes to the highly conserved DNA, DN34, in normal individuals and in patients with AS and PWS have been described. We report on a family in which first cousins are affected by AS and PWS as a result of a familial paracentric inversion of 15q11-q13. The results of the studies on this family demonstrate the differences in the methylation patterns in the 2 conditions and the phenomenon of genomic imprinting, whereby genetic information is expressed differently dependent on the parent of origin.

Further evidence for dominant inheritance at the chromosome 15q11-13 locus in familial Angelman syndrome.

Eleven patients with Angelman syndrome (AS) and their parents from 5 families have been studied with high resolution chromosome analysis and molecular probes from region 15q11-13 in an attempt to elucidate the mode of inheritance in familial AS. No deletions were detected. All families were informative with a combination of different short arm cytogenetic markers. All sets of sibs inherited the same maternal chromosome 15, but in 3 families sibs inherited different paternal 15s. Analysis of 6 polymorphic DNA markers supported the conclusion that AS sibs inherit the same maternal 15, but often different paternal 15s. These data make autosomal recessive inheritance at a 15q11-13 locus very unlikely and support the hypothesis that familial AS is due to maternal transmission of a mutation within 15q11-13.

Probable localisation of the Coffin-Lowry locus in Xp22.2-p22.1 by multipoint linkage analysis.

The Coffin-Lowry syndrome (McKusick No. 30360) is a rare genetically transmitted disorder characterized by severe mental retardation, "coarse" facial appearance, thick soft skin, tapering fingers, and progressive skeletal abnormalities. X-linked inheritance is implied since the males are severely affected with variably mild manifestations in carrier women. We have performed a linkage analysis with many X-linked RFLP markers in 4 families. Positive two-point lod scores were obtained with DXS28 (z(theta) = 2.00 at theta = 0.05) and DXS41 (z(theta) = 1.26 at theta = 0.10). We performed a 5-point linkage analysis using the LINKMAP program assuming that DXS16 and DXS43 are a single locus and using the following fixed map (distances in centimorgans): DXS85 - 18cM - (DXS16, DXS43) - 13cM - DXS41 - 5cM -DXS28. This gave a multipoint lod score of 3.41 for a localisation in Xp22.2-p22.1, between DXS43 and DXS41.

Refined localization of the branchiootorenal syndrome gene by linkage and haplotype analysis.

Branchiootorenal (BOR) syndrome is a common autosomal dominant form of hearing impairment previously mapped to 8q. This report refines the localization of the BOR syndrome gene by haplotype analysis to the interval flanked by markers D8S553 and D8S286. By multipoint linkage analysis, the disease locus most likely is flanked by markers D8S530 and D8S279.

An assessment of screening strategies for fragile X syndrome in the UK.

BACKGROUND: Fragile X syndrome is an inherited form of learning disability that was defined in the late 1970s by cytogenetic detection of an associated fragile site on the X chromosome (Xq27.3). Cytogenetic estimates of the prevalence of fragile X syndrome were as high as 1 in 1039 males but have since been revised downwards. Fragile X syndrome is associated with few medical problems and the subtle physical features make clinical diagnosis difficult. The unusual pattern of inheritance, delineated in the 1980s, was explained once the fragile X syndrome gene (FMR1) had been identified in 1991. This gene contains a highly variable repeat of the nucleotide triplet, cytosine-guanine-guanine (CGG). Fragile X syndrome is caused by a large expansion of this CGG repeat (full mutation) that leads to silencing of the FMR1 gene so no gene product (FMRP) is made. This is the ultimate cause of the learning disability that, in males, is sufficient to preclude independent living. Family studies show that all individuals with a full mutation inherit it from a female (usually unaffected) who carries either a full mutation or a premutation, a smaller repeat expansion (approximately 55-200 repeats) that is unstable on female transmission. The chance of a premutation expanding to a full mutation is positively associated with the size of the repeat (approximately 95% by 90 repeats) but only for female transmissions. When a man transmits a premutation, it remains a premutation; his children are, therefore, unaffected by overt learning difficulties. The potential for population screening or systematic case-finding and extended family testing exists because every unaffected mother of an affected child has a detectable CGG repeat expansion. Reliable prenatal diagnosis is possible in males. OBJECTIVES: To assess the feasibility and acceptability of population screening by addressing the following questions in the context of existing services for families with fragile X syndrome. (1) Is there a suitable test for all fragile X genotypes? (2) What are the UK population distribution of FMR1 repeat sizes, and the prevalence of full and premutations in both sexes? (3) What reliable information, in terms of the chance of an affected child, is available to women with premutations between 55 and 200 repeats? (4) What is the effect of a premutation on the person who carries it? (5) What information is available to women with intermediate alleles of 41 to 54-60 repeats? (6) How many affected people are diagnosed? (7) Given the practice of offering extended family testing (cascade testing), what is the population prevalence of 'as-yet-undiagnosed' female carriers of a full or premutation? What proportion of women at risk can be reached by cascade testing? (8) What are the costs of fragile X syndrome to an affected person and their family and to the NHS and society? (9) What is the attitude of families to the benefits and costs of a diagnosis of fragile X syndrome, and to the prospect of population screening? (10) What data are available from existing population screening programmes? (11) What alternatives to population screening exist and are these feasible? METHODS: A key aspect of the review process was to assemble a team with extensive first-hand experience of all aspects of fragile X syndrome, including affected families and the services they use, and a wide knowledge of the relevant literature. They had followed the critical discussions at all the biennial international workshops on fragile X syndrome, including a special session at the 7th International Workshop in 1995 at which an earlier (and substantially different) draft of this report was discussed. The biomedical literature review of 2429 papers was based on MEDLINE searches, extending to PsycINFO and BIDS for the psychological aspects of [fragile X syndrome] screening. Questionnaire-based information was obtained from the UK Fragile X Society and data were collected directly from all the regional clinical genetics centres in 1995 and 1998. RESULTS: Unlike cytogenetic approaches, DNA analysis can reliably determine the FMR1 CGG repeat number and detect full mutations; however, a combination of polymerase chain reaction and Southern blotting tests is required, which limits high throughput. There are UK population-based data on FMR1 repeat sizes of up to 60 repeats but insufficient to provide a reliable estimate of the prevalence of premutations (approximately 60-200 repeats). The few data and estimates in the literature of women carriers of the premutation range from 1 in 246 to 1 in 550. Two UK DNA-based estimates of the prevalence of males with the full mutation are 1 in 4090 (Coventry) and 1 in 5530 (Wessex). There are reasonable family-based data for the risk of expansion to a full mutation for the larger premutations but in the 50-69 repeat range the estimates are less secure. (ABSTRACT TRUNCATED)

Inheritance of parental chromosomes 15 in Angelman syndrome--implications for the family.

Molecular and cytogenetic studies in Angelman syndrome have demonstrated that the condition is genetically heterogeneous with a recurrence risk in certain families which may be as high as 50%. In an attempt to identify such families, cytogenetic polymorphisms of chromosome 15 have been studied in both affected and unaffected siblings of Angelman syndrome patients. The results suggest that in those cases with a cytogenetically visible 15q11q13 deletion where the recurrence risk is low, normal siblings inherit either maternal chromosome 15 homologue with impunity. By contrast, in cases where the proband does not demonstrate a cytogenetic 15q11q13 deletion, unaffected siblings tend to inherit the alternative homologue to that found in their affected siblings. These findings may have importance for genetic counseling.

Abnormal audiograms and elevated acoustic reflex thresholds in obligate carriers of autosomal recessive non-syndromic hearing loss.

Pure-tone audiograms and acoustic reflex thresholds were obtained in 24 presumed obligate carriers of autosomal recessive non-syndromic hearing loss and 30 sex and age appropriate control subjects, with a view to evaluating the prevalence of abnormalities on these tests in the two groups, and a possible link between the findings on the two tests, which may help to localize threshold deficits and/or abnormal configurations to different sections of the reflex arc. Six (25%) of the carriers and one control subject had abnormal audiograms, inferred to be of genetic aetiology through careful exclusion of environmental risk factors. Four additional carriers had acoustic reflex threshold abnormalities. None of the carriers had an abnormality on both tests. The audiometric configurations and acoustic reflex patterns of abnormality were diverse, and may be a reflection of the genetic heterogeneity in ARNSHL.