Wiley

Prader‐Willi syndrome (PWS) is characterized by hypotonia, obesity, hypogonadism, short stature, small hands and feet, mental deficiency, a characteristic face, and an interstitial deletion of the proximal long arm of chromosome 15 in about one‐half of the patients. The incidence is estimated to be about 1 in 25,000, and PWS is the most common syndromal cause of human obesity. DNA abnormalities, usually deletions or duplications of chromosome 15, have been identified in individuals with PWS with or without recognizable chromosome 15 deletions. Paternal origin of the chromosome 15 deletion by cytogenetic and DNA studies has been found in nearly all PWS individuals studied. No cytogenetic evidence for chromosome breakage has been identified, although an environmental cause (e.g., paternal hydrocarbon‐exposed occupations) of the chromosome 15 abnormality has been proposed. PWS patients with the chromosome 15 deletion are more prone to hypopigmentation compared with PWS individuals with normal chromosomes, but no other clinical differences are consistently identified between those with and without the chromosome deletion. Anthropometric, dermatoglyphic, and other clinical findings indicate homogeneity of PWS patients with the chromosome deletion and heterogeneity of the nondeletion patients. A review of our current understanding of the major clinical, cytogenetic, and DNA findings is presented, and clinical manifestations and cytogenetic abnormalities are summarized from the literature.

To identify genes responsible for the susceptibility for schizophrenia, and to test the hypothesis that schizophrenia is etiologically heterogeneous, we have studied 39 multiplex families from a systematic sample of schizophrenic patients. Using a complex autosomal dominant model, which considers only those with a diagnosis of schizophrenia or schizoaffective disorder as affected, a random search of the genome for detection of linkage was undertaken. Pairwise linkage analyses suggest a potential linkage (LRH = 34.7 or maximum lod score = 1.54) for one region (22q12‐q13.1). Reanalyses, varying parameters in the dominant model, maximized the LRH at 660.7 (maximum lod score 2.82). This finding is of sufficient interest to warrant further investigation through collaborative studies. © 1994 Wiley‐Liss, Inc.

Velo‐cardio‐facial syndrome (VCFS), an autosomal dominant disorder, is characterized by cleft palate, cardiac defects, learning disabilities and a typical facial appearance. Less frequently, VCFS patients have manifestations of the DiGeorge complex (DGC) including hypocalcemia, hypoplastic or absent lymphoid tissue and T‐cell deficiency suggesting that these 2 conditions share a common pathogenesis. Here, we report the results of cytogenetic and molecular studies of 15 VCFS patients. High ‐ resolution banding techniques detected an interstitial deletion of 22q11.21‐q11.23 in 3 patients. The remaining 12 patients had apparently normal chromosomes. Molecular analysis with probes from the DiGeorge Chromosome Region (DGCR) within 22q11 detected DNA deletions in 14 of 15 patients. In 2 families, deletions were detected in the affected parent as well as the propositus suggesting that the autosomal dominant transmission of VCFS is due to segregation of a deletion. Deletions of the same loci previously shown to be deleted in patients with DGC explains the overlapping phenotype of VCFS and the DGC and supports the hypothesis that the cause of these two disorders is the same. © 1992 Wiley‐Liss, Inc.

We investigated whether a woman's periconceptional use of a multivitamin containing folic acid was associated with a reduced risk for delivering offspring with a conotruncal heart defect or a limb deficiency. Data were derived from a population‐based case‐control study of fetuses and liveborn infants with conotruncal or limb defects among a 1987–88 cohort of births in California. Telephone interviews were conducted with mothers of 207 (87.0% of eligible) conotruncal cases, 178 (82.0%) limb defect cases, and of 481 (76.2%) randomly selected liveborn nonmalformed control infants. Reduced risks were observed for maternal use of multivitamins containing folic acid from one month before until two months after conception. Odds ratios and 95% confidence intervals for any compared to no multivitamin use were 0.70 (0.46–1.1) for conotruncal defects and 0.64 (0.41–1.0) for limb defects. Controlling for maternal race/ethnicity, age, education, gravidity, alcohol use, and cigarette use resulted in a further reduction to the odds ratio for conotruncal defects, 0.53 (0.34–0.85), but not for limb defects. Among non‐vitamin using women, consumption of cereal containing folic acid was also associated with reduced risks for both defects. Women who take multivitamins have 30–35% lower risk of delivering offspring with either conotruncal or limb defects. This association may not be attributable to folic acid specifically, but may be a consequence of other multivitamin components, or some unknown behaviors that highly correlate with regular use of a multivitamin. However, should the association prove causal, it offers an important opportunity for preventing thousands of serious birth defects. © 1995 Wiley‐Liss, Inc.

From a series of 1265 individuals with different craniosynostoses hospitalized between 1976 and 1993, 260 probands with nonsyndromic unilateral (181) or bilateral (79) coronal synostosis were analysed. The prevalence of craniosynostoses was estimated as 1 in 2100 children. In the group of coronal synostosis, family history was obtained on 192 probands in 180 pedigrees. The male:female ratio was 1:2. The average paternal age was 32.7 ± 6.4 years, which is significantly higher than normal. In 26 of the 180 pedigrees, a high degree of familial aggregation was observed, giving a 14.4% figure of familial cases. The bicoronal synostoses were significantly more often familial than the unicoronal synostoses. Segregation analysis of these families leads to the conclusion that coronal synostosis is transmitted as a dominant disorder with 0.60 penetrance and 61% of sporadic cases. © 1995 Wiley‐Liss, Inc.

We report on six infants with a neonatally lethal malformation syndrome of hypothalamic hamartoblastoma, postaxial polydactyly, and imperforate anus. Some, but not all, patients had laryngeal cleft, abnormal lung lobulation, renal agenesis and/or renal dysplasia, short 4th metacarpals, nail dysplasia, multiple buccal frenula, hypoadrenalism, microphallus, congential heart defect, and intrauterine growth retardation. The infants also had hypopituitarism and hypoadrenalism.

All were sporadic cases, parents were not consanguineous, chromosomes were apparently normal. Family histories were unremarkable. There was insecticide and/or herbicide exposure in several of the cases, but no exposures were common to all 6 mothers. Five of the patients were born within an 8‐month period, but all in different geographic locations. It is postulated that this is a previously apparently unreported syndrome of presently unknown cause.

One hundred eighteen cases of nevoid basal cell carcinoma syndrome (NBCCS, Gorlin's syndrome or basal cell nevus syndrome) are presented in this study. In aiming to ascertain all the affected families in Australia, we have examined the largest series to date. Relative frequencies of associated complications are presented and compared with those of the recent English survey by Evans et al. [J Med Genet 30:460–464, 1993]. The frequencies of most manifestations are similar. However, one major difference is that the multiple basal cell carcinomas are manifest from an earlier age in the Australian population, which probably reflects greater exposure to ultraviolet radiation. Of the 64 families ascertained, 37 represented simplex cases, and, accordingly, the apparent new mutation rate is surprisingly high (14–81%) given the lack of impact of NBCCS on reproductive capabilities. There is some evidence to suggest that this may be attributable to anticipation. © 1994 Wiley‐Liss, Inc.

Using a systematically ascertained sample of 57 families, each having 2 or more members with a consensus diagnosis of schizophrenia (DSM‐III‐R criteria), we have carried out linkage studies of 520 loci, covering approximately 70% of the genome for susceptibility loci for schizophrenia. A two‐stage strategy based on lod score thresholds from simulation studies of our sample identified regions for further exploration. In each region, a dense map of highly informative dinucleotide repeat polymorphisms (heterozygosity greater than .70) was analyzed using dominant, recessive, and “affected only” models and nonparametric sib pair identity‐by‐descent methods. For one region, 8p22‐p21, affected sib‐pair analyses gave a P value = .0001, corresponding to a lod score approximately equal to 3.00. For 8p22–p21, the maximum two‐point lod score occurred using the “affected only” recessive model (Z_MAX = 2.35; θ_M = θ_F); allowing for a constant sex difference in recombination fractions found in reference pedigrees, Z_MAX = 2.78 (θ_M/θ_F = 3). For a second region, 3p26–p24, the maximum two‐point lod score was 2.34 (“affected only” dominant model), and the affected sib‐pair P value was .01. These two regions are worthy of further exploration as potential sites of susceptibility genes for schizophrenia. © 1995 Wiley‐Liss, Inc.

Autistic disorder (AutD) is a neurodevelopmental disorder characterized by significant impairment in social, communicative, and behavioral functioning. A genetic basis for AutD is well established with as many as 10 genes postulated to contribute to its underlying etiology. We have completed a genomic screen and follow‐up analysis to identify potential AutD susceptibility loci. In stage one of the genome screen, 52 multiplex families (two or more AutD affected individuals/family) were genotyped with 352 genetic markers to yield an approximately 10 centimorgan (cM) grid, inclusive of the X chromosome. The selection criterion for follow‐up of interesting regions was a maximum heterogeneity lod score (MLOD) or a maximum nonparametric sib pair lod score (MLS) of at least 1.0. Eight promising regions were identified on chromosomes 2, 3, 7, 15, 18, 19, and X. In the stage two follow‐up study we analyzed an additional 47 multiplex families (total = 99 families). Regions on chromosomes 2, 3, 7, 15, 19, and X remained interesting (MLOD ≥ 1.0) in stage two analysis. The peak lod score regions on chromosomes 2, 7, 15, 19, and X overlap previously reported peak linkage areas. The region on chromosome 3 is unique. © 2001 Wiley‐Liss, Inc.

We investigated the effect of incorporating information about proband and parental structural language phenotypes into linkage analyses in the two regions for which we found the highest signals in our first‐stage affected sibling pair genome screen: chromosomes 13q and 7q. We were particularly interested in following up on our chromosome 7q finding in light of two prior reports of linkage of this region to developmental language disorder, since one of the diagnostic criteria for autism is absent or abnormal language development. We hypothesized that if the language phenotype were genetically relevant to linkage at the chromosome 7q locus, then incorporating parents phenotypes would increase the signal at that locus, and most of the signal would originate from the subset of families in which both probands had severe language delay. The results support these hypotheses. The linkage signals we obtained on chromosome 7q as well as at least one signal on chromosome 13q are mainly attributable to the subgroup of families in which both probands had language delay. This became apparent only when the parents’ history of language‐related difficulties was also incorporated into the analyses. Although based on our data, we were not able to distinguish between epistasis or heterogeneity models, we tentatively concluded that there may be more than one autism susceptibility locus related to language development. © 2001 Wiley‐Liss, Inc.