bluuebunny/crossref_metadata_2025 huggingface dataset:
Neurofibromatosis 2 (NF2): Clinical characteristics of 63 affected individuals and clinical evidence for heterogeneity
Authors: Parry Dilys M. , Eldridge Roswell , Kaiser‐Kupfer Muriel I. , Bouzas Evrydiki A. , Pikus Anita , Patronas Nicholas
Published: June 2005

To determine the spectrum of manifestations in neurofibromatosis 2 (NF2) and to assess possible heterogeneity, we evaluated 63 affected individuals from 32 families. Work‐up included skin and neurologic examinations, audiometry, a complete ophthalmology examination with slit‐lamp biomicroscopy of the lens and fundus, and gadolinium‐enhanced MRI of the brain and, in some, of the spine. Mean age‐at‐onset in 58 individuals was 20.3 years; initial symptoms resulted from vestibular schwannomas (44.4%), other CNS tumors (22.2%), skin tumors (12.7%), and ocular manifestations including cataracts and retinal hamartomas (12.7%). Five asymptomatic individuals were diagnosed through screening. Vestibular schwannomas were documented in 62 individuals (98.4%); other findings included cataracts (81.0%), skin tumors (67.7%), spinal tumors (67.4%), and meningiomas (49.2%). Usually, clinical manifestations and course were similar within families but differed among families. To assess possible heterogeneity, we assigned affected individuals to three proposed subtypes (representing mild, intermediate, and severe NF2) based on age‐at‐onset, presence or absence of CNS tumors other than vestibular schwannomas, and presence or absence of retinal hamartomas. Comparisons among the three subtypes for many clinical parameters demonstrated that patients in the mild subtype differed from those in the other two subtypes for most parameters, but that none of the parameters distinguished patients in the intermediate subtype from those in the severe subtype. Thus, there are likely two rather than three subtypes of NF2. Classification of patients to subtype may aid in counseling about long‐term prognosis and in formulating individualized guidelines for medical surveillance. © 1994 Wiley‐Liss, Inc.

This article is a U.S. Government work and, as such, is in the public domain in the United States of America

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Hypoparathyroidism as the major manifestation in two patients with 22q11 deletions
Authors: Scirè Giuseppe , Dallapiccola Bruno , Iannetti Paola , Bonaiuto Francesco , Galasso Cinzia , Mingarelli Rita , Boscherini Brunetto
Published: June 2005

We report on two adolescents with 22q11 deletion. Their main clinical manifestation was chronic symptomatic hypocalcemia secondary to hypoparathyroidism, together with seizures and cerebral calcifications. Neither congenital cardiac abnormality nor T cell deficiency were detected. The pheno‐typic manifestations of the observed patients were consistent with velo‐cardio‐facial syndrome (VCFS).

A microdeletion of chromosome region 22q11 has been demonstrated in approximately 90% of DiGeorge syndrome (DGS) patients and in 75% of VCFS patients; the association of the deletion with a wide spectrum of clinical findings suggests the existence of a contiguous gene syndrome.

The presence of certain traits of DGS/VCFS should lead to investigations of the parathyroid function and molecular analysis of the 22q11 region hybridization studies. © 1994 Wiley‐Liss, Inc.
Monozygotic twins discordant for spondylocostal dysostosis
Authors: Van Thienen Marie‐Noëlle , Van der Auwera Bart J.
Published: June 2005

Spondylocostal dysostosis (SCD) is a rare skeletal dysplasia with clinical and radiological manifestations, consisting of short neck and trunk, barrel‐shaped chest, protuberant abdomen, scoliosis and abnormalities of vertebral segmentation and of the ribs. Both autosomal recessive and autosomal dominant inheritance have been described. We report on monozygotic twins discordant for the syndrome, either due to a post‐zygotic mutation or development of a phenocopy. To our best knowledge, this is the fourth report of SCD in identical twins, and the first one of discordance in monozygotic twins. © 1994 Wiley‐Liss, Inc.
On the inheritance of the split hand/split foot malformation
Authors: Zlotogora Joël
Published: June 2005

Analysis of families with non‐syndromal split hand/split foot (SHSF) confirms the existence of 2 distinct entities, most probably caused by at least 2 different autosomal dominant genes. In the families in which the SHSF malformation is non‐syndromal and limited to the hands and feet (type I), the pattern of inheritance is of a regular autosomal dominant gene with a high penetrance (96%). In families in which at least one individual has other limb malformations and SHSF (type II), the transmission is often unusual. In most families, the gene is non‐penetrant, sometimes for generations, before the birth of the first affected individual. Thereafter, among the descendants of affected individuals, the penetrance is reduced (66%), suggesting the possible existence of another gene which controls the appearance of the clinical manifestations. The possibility that SHSF associated with other limb malformations is a disorder caused by trinucleotide repeat instability is raised. © 1994 Wiley‐Liss, Inc.
Partial X chromosome trisomy with functional disomy of Xp due to failure of X inactivation
Authors: Gustashaw Karen M. , Zurcher Vickie , Dickerman Lois H. , Stallard Richard , Willard Huntington F.
Published: June 2005

A 5‐month‐old girl with mild phenotypic abnormalities, developmental delay, and seizures was found to have the de novo kary‐otype 46,XX,−13,+der(13)t(X;13)(p21.2;p11.1). The partial trisomy of Xp21.2 → pter was confirmed with fluorescence in situ hybridization, using an X chromosome painting probe and several cosmid and YAC probes for Xp sequences. Replication banding showed that one of the structurally normal X chromosomes was late‐replicating, but that the Xp segment of the der(13) was early‐replicating in all cells examined. Since segments of the X chromosome separated from the X inactivation center in Xql3.2 cannot undergo X inactivation, the result is functional disomy of distal Xp. As the loss of short arm material from chromosome 13 is not considered to be clinically significant, the genomic imbalance of Xp expressed in this patient most likely accounts for her abnormal phenotype. © 1994 Wiley‐Liss, Inc.
Holoprosencephaly associated with caudal dysgenesis: A clinical‐epidemiological analysis
Authors: Martínez‐Frías María Luisa , Bermejo Eva , García Angel , Galín Enrique , Prieto Luis
Published: June 2005

We have studied 9 cases with the combination of some form of holoprosencephaly and any degree of caudal dysgenesis. The cases were identified through the Spanish Collaborative Study of Congenital Malformations (ECEMC). Of the 9 cases, 6 infants had an aneuploidy syndrome, one had Meckel syndrome, and 2 cases were of unknown etiology. We determined that the prevalence figure for the association of both conditions in the same child was 0.08 per 10,000 livebirths, and 18.8 times higher for stillbirths (i.e., 1.50/10,000). This prevalence is significantly higher than what would be expected by Chance. © 1994 Wiley‐Liss, Inc.
Hypertrichosis “cubiti” with facial asymmetry
Authors: Edwards Matthew J. , Crawford Anthony E. , Jammu Vapinder , Wise Graham
Published: June 2005

Hypertrichosis of the elbow region may be the only abnormality in hypertrichosis cubiti (hairy elbow syndrome). Only 6 cases have been reported; 2 Amish sibs also had additional short stature and, in the most recent case report, a patient had asymmetry of the face, generalized hypotonia, ptosis, epicanthic folds, highly arched palate, and delayed growth and development. The child reported here also had asymmetry of facial growth, ptosis, delayed speech development, and hypertrichosis in a patchy distribution which included the elbow regions, face, trunk, and thighs. There was no family history of hypertrichosis, and the karyotype of cultured fibroblasts was normal in the skin of an area of hypertrichosis. These patients appear to have a distinct condition compared to other hypertrichosis syndromes. © 1994 Wiley‐Liss, Inc.
Second locus for Hirschsprung disease/Waardenburg syndrome in a large Mennonite kindred
Authors: Dow Eleanor , Cross Sean , Wolgemuth Debra J. , Lyonnet Stanislas , Mulligan Lois M. , Mascari Maria , Ladda Roger , Williamson Robert
Published: June 2005

We have studied a large Mennonite kindred in which 20 members were affected with Hirschsprung disease (HSCR), 5 of whom had one or more manifestations of Waardenburg syndrome (WS) type II (WS2). Eleven additional relatives had signs of WS2 without HSCR. Since HSCR and WS2 each represent perturbations of neural crest migration/differentiation, this large pedigree with apparent cosegregation of HSCR and WS2 offered an opportunity to search for linkage between these loci, candidate genes, and random DNA markers, particularly in view of recent discoveries of genes for Waardenburg syndrome type I (WS1) and Hirsch‐sprung disease (c‐ret). We have examined the following possible linked markers in 69 relatives in this family: the c‐ret gene (HSCR); the human PAX3 gene (HuP2) on chromosome 2q (WS1) and placental alkaline phosphatase (ALPP) on chromosome 2q (linked to WS1); argininosuccinate synthetase (ASS) on chromosome 9q, close to ABO blood groups which have shown weak linkage to WS; and the β1 GABA receptor gene (GABARB1) on chromosome 4q13‐ll, close to c‐kit, deletions of which cause piebaldism. Linkage between any of these loci and HSCR/WS in this kindred was excluded, demonstrating that there is at least one further locus for HSCR other than c‐ret. © 1994 Wiley‐Liss, Inc.
Female infant with oncocytic cardiomyopathy and microphthalmia with linear skin defects (MLS): A clue to the pathogenesis of oncocytic cardiomyopathy?
Authors: Bird Lynne M. , Krous Henry F. , Eichenfield Lawrence F. , Swalwell Christopher I. , Jones Marilyn C.
Published: June 2005

A infant girl had red stellate skin lesions on the cheeks and neck, and mildly short palpebral fissures. Her skin abnormality was typical of microphthalmia with linear skin defects (MLS), a newly recognized syndrome consisting of congenital linear skin defects and ocular abnormalities in females monosomic for Xp22. She died suddenly and unexpectedly at age 4 months; the cause of death was ascribed to oncocytic cardiomyopathy. Oncocytic cardiomyopathy occurs only in young children, who present with refractory arrhythmias leading to cardiac arrest. The coexistence of two rare conditions, one of which is mapped to the X chromosome, and an excess of affected females with oncocytic cardiomyopathy, make it likely that oncocytic cardiomyopathy is also X‐linked, with Xp22 being a candidate region. Overlapping manifestations in the two conditions (ocular abnormalities in cases of oncocytic cardiomyopathy and arrhythmias in MLS) offer additional support for this hypothesis. © 1994 Wiley‐Liss, Inc.
Ectodermal dysplasias: A clinical classification and a causal review
Authors: Pinheiro Marta , Freire‐Maia Newton
Published: June 2005

We present a causal review of 154 ectodermal dysplasias (EDs) as classified into 11 clinical subgroups. The number of EDs in each subgroup varies from one to 43. The numbers of conditions due to autosomal dominant, autosomal recessive, and X‐linked genes are, respectively, 41, 52, and 8. In 53 conditions cause is unknown; 35 of them present some causal (genetic) suggestion. © 1994 Wiley‐Liss, Inc.
De novo 17q paracentric inversion mosaicism in a patient with Beemer‐Langer type short rib‐polydactyly syndrome with special consideration to the classification of short rib polydactyly syndromes
Authors: Chen Harold , Mirkin David , Yang Samuel
Published: June 2005

A de novo 17q paracentric inversion mosaicism is detected in a fetus with type IV short rib (polydactyly) syndrome (Beemer‐Langer). The cytogenetic finding in our case suggests a possible location of the gene or cluster of linked genes responsible for SR (P) S type IV to 17q21 or 17q23. Since this chromosome abnormality has not been described in short rib polydactyly syndromes and the existence of type IV SR (P) S has been controversial, the literature of this entity is reviewed with special consideration to the classification of short rib polydactyly syndromes. © 1994 Wiley‐Liss, Inc.
Polydactyly in a carrier of the gene for the meckel syndrome
Authors: Nelson John , Nevin Norman C. , Hanna E. Jennifer
Published: June 2005

Much of the Meckel syndrome literature has been concerned with the criteria for diagnosis but little has been said concerning heterozygote expression. We describe 3 affected brothers whose father and his paternal first cousin had postaxial polydactyly of both feet. A review of the literature was undertaken with regard to possible manifesting heterozygotes. We conclude that it is important to examine the relatives of patients with the Meckel syndrome for mild abnormalities, as these may be evidence of a manifesting heterozygote. Such information may be useful for genetic counselling. © 1994 Wiley‐Liss, Inc.
Distinguishing genetic disease and genetic susceptibility
Authors: Wachbroit Robert S.
Published: June 2005

With the increasing awareness of the involvement of genetic factors in disease, questions arise as to what distinguishes genetic from non‐genetic disease, and what constitutes a genetic susceptibility. A general framework, reflecting the structure of biological explanations, is presented in which such distinctions can be made. We conclude that such distinctions are objective and are based on the biological facts; they are not “social constructions” nor do they presuppose resolution of philosophical problems regarding causation. © 1994 Wiley‐Liss, Inc.
Clinical spectrum and genetic studies of Fukuyama congenital muscular dystrophy
Authors: Yoshioka Mieko , Kuroki Shigekazu
Published: June 2005

The association of congenital muscular dystrophy (CMD) with type II lissencephaly and ocular anomalies is found in Fukuyama CMD (FCMD), the Walker‐Warburg syndrome (WWS), and muscle‐eye‐brain disease (MEBD). The classification of these disorders remains controversial. Between 1972 and 1992, we performed clinical and genetic studies in 41 families of FCMD, which is particularly frequent in Japan. Nine families (22%) had multiple affected children (“familial” FCMD). The other 32 families had only one affected child (“sporadic” FCMD). Parental consanguinity was documented in 5 sporadic FCMD families and in none of the familial cases. In total, 48 patients, including 7 sib pairs, were evaluated with regard to maximum motor ability, mental and convulsion states, cranial CT or MRI findings, and EEG and ophthalmological data. A difference between the sibs in motor ability was apparent in 4 families. Mental status also showed wide variation. Two of 7 sib pairs differed in EEG findings. The familial FCMD patients showed relatively more severe motor disability than that in the sporadic FCMD patients, while in mental and convulsion states no significant difference was found in both groups. Interestingly, in one family hydrocephalus was found in only one of the sibs. In addition, this patient showed encephalocele and retinal detachment at birth. Based on these observations, we consider the clinical spectrum of FCMD to be much broader than previously described and to overlap with that of “mild” WWS and of MEBD. © 1994 Wiley‐Liss, Inc.
Confirmation that the conotruncal anomaly face syndrome is associated with a deletion within 22q11.2
Authors: Matsuoka Rumiko , Takao Atsuyoshi , Kimura Misa , Imamura Shin‐ichiro , Kondo Chisato , Joh‐o Kunitaka , Ikeda Kazuo , Nishibatake Makoto , Ando Masahiko , Momma Kazuo
Published: June 2005

The so‐called “conotruncal anomaly face syndrome” (CTAFS) is characterized by a peculiar facial appearance associated with congenital heart disease (CHD), especially cardiac outflow tract defects such as tetralogy of Fallot (TOF), double outlet right ventricle (DORV), and truncus arteriosus (TAG). CTAFS and the DiGeorge anomaly (DGA) have many similar phenotypic characteristics, suggesting that they share a common cause. In many cases DGA is known to be associated with monosomy for a region of chromosome 22q11.2. Fifty CTAFS patients and 10 DGA patients, 11 parents couples and 10 mothers of CTAFS patients, and 3 parents couples and 2 mothers of DGA patients were examined by fluorescent in situ hybridization (FISH) using the N25 (D22S75) DGCR probe (Oncor). Monosomy for a region of 22q11.2 was found in 42 CTAFS, 9 DGA, 4 mothers, and 1 father who had CTAF without CHD. The remaining 8 CTAFS patients, 1 DGA patient and 1 mother who had questionable CTAF without CHD, showed no such chromosome abnormality. For the control, 60 patients who had CHD without CTAF or other know malformation syndromes were examined and had no deletion of 22q11.2. Therefore, we conclude that CTAFS is a part of the CATCH 22 syndrome; cardiac defects, abnormal faces, thymic hypoplasia, cleft palate, and hypocalcemia (CATCH) resulting from 22q11.2 deletions. © 1994 Wiley‐Liss, Inc.
Aplasia cutis congenita with epibulbar dermoids: Further evidence for syndromic identity of the ocular ectodermal syndrome
Authors: Gardner Jessica , Viljoen Denis
Published: June 2005

We have investigated 2 young South African girls with aplasia cutis congenita, epibulbar dermoids, and strabismus. This unique association of anomalies was first documented in two unrelated boys by Toriello et al. [1993: Am. J. Med. Genet. 45:764–766]. Our clinical and histological findings are markedly similar, and we think this to be the second report of individuals with this rare syndrome. © 1994 Wiley‐Liss, Inc.
Oculo‐ectodermal syndrome: A new case
Authors: Evers Mirjam E. J. W. , Dijkman‐Neerincx Regina H. M. , Hamel Ben C. J.
Published: June 2005

We report on a girl with aplasia cutis congenita, epibulbar dermoids, and macrocephaly. To our opinion she has the same ocular‐ectodermal syndrome as described by Toriello et al. [Am J Med Genet 45: 764–766, 1993]. © 1994 Wiley‐Liss, Inc.
Screening the dystrophin gene suggests a high rate of polymorphism in general but no exonic deletions in schizophrenics
Authors: Lindor Noralane M. , Sobell Janet L. , Heston Leonard L. , Thibodeau Stephen N. , Sommer Steve S.
Published: June 2005

The dystrophin gene, located at chromosome Xp21, was evaluated as a candidate gene in chronic schizophrenia in response to the report of a large family in which schizophrenia cosegregated with Becker muscular dystrophy [Zatz et aI., 1991: Am J Hum Genet 49: A364; 1992: J Med Genet 30(2):131–134]. Genomic DNA from 94 men with chronic schizophrenia was evaluated by Southern blot analysis using cDNA probes that span exons 1–59. No exonic deletions were identified. An unexpectedly high rate of polymorphism was calculated in this study and two novel polymorphisms were found, demonstrating the usefulness of the candidate gene approach even when results of the original study are negative. © 1994 Wiley‐Liss, Inc.
Bipolar disorder and the pseudoautosomal region: An association study
Authors: Parsian Abbas , Todd Richard D.
Published: June 2005

From family, adoption, and twin studies it is clear that genetic factors play an important role in the etiology of bipolar disorder (McGuffin and Katz: The Biology of Depression, Gaskell, London, 1986). Recently Yoneda et al. (Am J Hum Genet 51:1172–1173, 1992) reported an association between an allele (A4) of a VNTR marker (DXYS20) for the pseudoautosomal region and bipolar disorder in a Japanese population. In order to test for this association in a Caucasian population, we have typed a sample of 52 subjects with bipolar disorder and 61 normal controls. The bipolar subjects are probands of multiple incidence families. The normal controls are an epidemiologically ascertained sample of middle‐aged, unrelated individuals. The two groups were matched for sex and ethnic background. There were no significant differences in the allele or genotype frequencies of DXYS20 between the two groups. In particular, there was no significant difference in the frequency of the A4 allele in normal controls and bipolar patients (0.377 vs. 0.317, respectively). The prevalence of the A4 allele in bipolar patients and normal controls was 0.567 and 0.622, respectively. We were not able to replicate the results of the Yoneda et al. (1992) study. © 1994 Wiley‐Liss, Inc.
Genetics of autism: Characteristics of affected and unaffected children from 37 multiplex families
Authors: Spiker Donna , Lotspeich Linda , Kraemer Helena C. , Hallmayer Joachim , McMahon William , Petersen P. Brent , Nicholas Peter , Pingree Carmen , Wiese‐Slater Susan , Chiotti Carla , Lee Wong Dona , Dimicelli Susan , Ritvo Edward , Cavalli‐Sforza Luigi L. , Ciaranello Roland D.
Published: June 2005

Evidence from twin and family studies strongly suggests that genetic factors play a prominent role in the etiology of some cases of infantile autism. Genetic factors would be expected to be especially strong in families with multiple autistic members (multiplex families). This report describes the identification and evaluation of 44 families with two or more autistic children collected as part of a genetic linkage study in autism. Families were referred with a presumptive classification of multiplex autism. Children referred as autistic, as well as their presumptively normal siblings, were assessed using the Autism Diagnostic Interview (ADI) and the Autism Diagnostic Observation Scale (ADOS). Thirty‐seven of the 44 families (87%) had at least two children who met diagnostic criteria for autism on the ADI. Of the total group of 117 children evaluated in those families, 83 (71%) met all ADI criteria and could be unambiguously classified as autistic (affected), 26 (22%) met none of the ADI criteria and were classified as not autistic (unaffected), and 8 (7%) were classified as uncertain because they met one or more but not all of the ADI cutpoints. Autistic siblings were not significantly concordant for most autism characteristics, for IQ, or for verbal ability. Significant concordances were found, however, for behaviors related to rituals and repetitive play, and for social impairments in the expression and understanding of facial expressions of emotion. The results of this study suggests two major points: first, there does not appear to be a highly variable autistic phenotype expressed in multiplex families; in the vast majority of cases, children are either clearly affected or clearly unaffected, so that linkage analysis should not be complicated by a large number of ambiguous or uncertain cases. Second, multiplex families do not appear to associate into subgroups defined by clustering of specific autism behaviors. © 1994 Wiley‐Liss, Inc.
Follow‐up of a report of a potential linkage for schizophrenia on chromosome 22q12‐q13.1: Part 2
Authors: Pulver Ann E. , Karayiorgou Maria , Lasseter Virginia K. , Wolyniec Paula , Kasch Laura , Antonarakis Stylianos , Housman David , Kazazian Haig H. , Meyers Deborah , Nestadt Gerald , Ott Jurg , Liang Kung‐Yee , Lamacz Malgorzata , Thomas Marion , Childs Barton , Diehl Scott R. , Wang Shengbiao , Murphy Bernadette , Sun Cui‐E , O'Neill F. Anthony , Nie Li , Sham Pak , Burke John , Duke Betty W. , Duke Fiona , Kipps Barbara R. , Bray Joseph , Hunt Wanda , Shinkwin Rosmarie , Nuallain Maurin Ni , Su Ying , Maclean Charles J. , Walsh Dermot , Kendler Kenneth S. , Gill Michael , Vallada Homero , Mant Rebecca , Asherson Philip , Collier David , Parfitt Elizabeth , Roberts Enriquetta , Nanko Shin , Walsh Cathy , Daniels Johanna , Murray Robin , McGuffin Peter , Owen Mike , Laurent Claudine , Dumas Jean‐Baptiste , d'Amato Thierry , Jay Maurice , Martinez Maria , Campion Dominique , Mallet Jacques
Published: June 2005

A collaboration involving four groups of investigators (Johns Hopkins University/Massachusetts Institute of Technology; Medical College of Virginia/The Health Research Board, Dublin; Institute of Psychiatry, London/University of Wales, Cardiff; Centre National de la Recherche Scientifique, Paris) was organized to confirm results suggestive of a schizophrenia susceptibility locus on chromosome 22 identified by the JHU/MIT group after a random search of the genome. Diagnostic, laboratory, and analytical reliability exercises were conducted among the groups to ensure uniformity of procedures. Data from genotyping of 3 dinucleotide repeat polymorphisms (at the loci D22S268, IL2RB, D22S307) for a combined replication sample of 256 families, each having 2 or more affected individuals with DNA, were analysed using a complex autosomal dominant model. This study provided no evidence for linkage or heterogeneity for the region 22q12‐q13 under this model. We conclude that if this region confers susceptibility to schizophrenia, it must be in only a small proportion of families. Collaborative efforts to obtain large samples must continue to play an important role in the genetic search for clues to complex psychiatric disorders such as schizophrenia. © 1994 Wiley‐Liss, Inc.
Progress in a genome scan for linkage in schizophrenia in a large Swedish kindred
Authors: Barr C. L. , Kennedy J. L. , Pakstis A. J. , Wetterberg L. , Sjögren B. , Bierut L. , Wadelius C. , Wahlström J. , Martinsson T. , Giuffra L. , Gelernter J. , Hallmayer J. , Moises H. W. , Kurth J. , Cavalli‐Sforza L. L. , Kidd K. K.
Published: June 2005

Genetic linkage studies of a kindred from Sweden segregating for schizophrenia have been performed using a genetic model (autosomal dominant, f = 0.72, q = 0.02, phenocopies = 0.001) as described in Kennedy et al., 1988. Analyses of the restriction fragment length polymorphism (RFLP), allele‐specific oligonucleotides (ASO), and short tandem repeat (STR also called microsatellite) data for 180 polymorphisms (individual probe‐enzyme, ASO, or STR systems) at 155 loci have been completed using the MLINK and LIPED programs. Linkage to schizophrenia was excluded, under the given model, at 47 loci; indeterminate lod scores occurred at 108 loci. The total exclusion region across 20 chromosomes is estimated at 330 cM; 211 cM excluded by pairwise analyses and 119 cM previously excluded by multipoint analyses (Kennedy et al., 1989: Schizophr Bull 15:383–391; Moises et al. 1991: Genet Epidemiol 2:99–110; Hallmayer et al., 1992: Arch Gen Psychiatry 49:216–219). © 1994 Wiley‐Liss, Inc.
Analysis of chromosome 22 markers in nine schizophrenia pedigrees
Authors: Coon Hilary , Holik John , Hoff Mark , Reimherr Fred , Wender Paul , Myles‐Worsley Marina , Waldo Merilyne , Freedman Robert , Byerley William
Published: June 2005

Previous results of a genome‐wide survey for schizophrenia susceptibility genes in nine multiplex families indicated a possible region of linkage on chromosome 22. We therefore tested for linkage using ten highly polymorphic chromosome 22 DNA markers. Lod score analyses were suggestive of linkage for several markers on the distal end of the chromosome; however, no lod score exceeded 3 assuming either autosomal dominant or autosomal recessive transmission. The highest lod score was 2.09 (theta = 0.10) for marker D22S276 under autosomal recessive inheritance. Based on simulation analyses, this result is unlikely to represent a false positive. Analyses using information from affected individuals only resulted in reduced lod scores, with a maximum of 1.40 (theta = 0.05) for D22S276 assuming autosomal recessive inheritance. Two nonparametric methods, sib pair analysis and the Affected‐Pedigree‐Member method, also yielded suggestive but inconclusive findings; results were positive, but strict thresholds of significance were not met. Additionally, we tested one candidate gene, the Arylsulfatase A gene, located in the region of 22q13.31‐qter. Results were again inconclusive, though the DNA marker available for this gene was a 2‐allele RFLP with heterozygosity of 0.5, and therefore not maximally informative. Further investigation of this chromosomal region and this and other candidate genes may be warranted. © 1994 Wiley‐Liss, Inc.
Turning point in the design of linkage studies of schizophrenia
Authors: Cloninger C. Robert
Published: June 2005

Despite extensive genomic scans, linkage studies of multiplex pedigrees have been unable to produce replicable evidence of genes predisposing to schizophrenia. This indicates that it is unlikely that a single gene accounts for a majority of cases of schizophrenia, even in multiplex pedigrees. It is most likely that schizophrenia is caused by the nonlinear interaction of multiple genetic and environmental factors influencing brain development and function. This conclusion has strong implications for the design of linkage and association studies. Recently designed linkage studies involve several improvements to deal with extensive locus heterogeneity and multiplicative interaction. These improvements include much larger samples of pedigrees, systematic ascertainment and sequential extension rules, and standardized procedures at multiple sites to facilitate collaboration and replication. Future improvements are likely to require advances in the assessment of clinical and neurobiological variability in multiplex pedigrees, more systematic environmental assessment, and advances in analytic methods to deal with multiplicative interaction. Rather than focusing only on schizophrenia as one or more discrete disorders, future linkage efforts should also consider the etiology of individual clinical syndromes or dimensional components of risk that interact to cause the complex pattern of syndromal comorbidity observed within schizophrenics and their families. © 1994 Wiley‐Liss, Inc.
Brain anomalies in velo‐cardio‐facial syndrome
Authors: Mitnick Robin J. , Bello Jacqueline A. , Shprintzen Robert J.
Published: June 2005

Magnetic resonance imaging of the brain in 11 consecutively referred patients with velo‐cardio‐facial syndrome (VCF) showed anomalies in nine cases including small vermis, cysts adjacent to the frontal borns, and small posterior fossal. Focal signal hyperintensities in the white matter on long TR images were also noted. The nine patients showed a variety of behavioral abnormalities including mild developmental delay, learning disabilities, and characteristic personality traits typical of this common multiple anomaly syndrome which has been related to a microdeletion at 22q11. Analysis of the behavioral findings showed no specific pattern related to the brain anomalies, and the patients with VCF who did not have detectable brain lesions also had behavioral abnormalities consistent with VCF. The significance of the lesions is not yet known, but the high prevalence of anomalies in this sample suggests that structural brain abnormalities are probably common in VCF. © 1994 Wiley‐Liss, Inc.
Mood disorder service genetic database: Morbidity risks for mood disorders in 3,942 first‐degree relatives of 671 index cases with single depression, recurrent depression, bipolar I, or bipolar II
Authors: Sadovnick A. D. , Remick R. A. , Lam R. , Zis A. P. , Yee I. M. L. , Huggins M. J. , Baird P. A.
Published: June 2005

There is increasing evidence that genetic factors play a role in the etiology of mood disorders. As a result, relatives of affected individuals are more often asking about their own risks to develop a mood disorder.

From 1988 to 1990, all consecutive, unrelated inpatients and outpatients (index cases) presenting to the Mood Disorders Service, Department of Psychiatry, University of British Columbia, had detailed family histories taken, thus creating the Mood Disorders Service Genetic Database. Diagnoses for index cases and their first‐degree relatives were made according to Research Diagnostic Criteria and Family History Research Diagnostic Criteria respectively.

Morbidity risks for mood disorders were calculated for first‐degree relatives (parents, siblings, children—aged 10 and above) of all index cases with a diagnosis of single depression, recurrent depression, bipolar I, or bipolar II disorder. Morbidity risks were calculated using the maximum likelihood approach. Morbidity risk data are presented according to the sex and diagnosis for the index case in an easy reference format for risk counselling. The risks are presented twice, including and excluding data for “high‐risk” families whose genetic pedigree is suggestive of “autosomal dominant” inheritance. © 1994 Wiley‐Liss, Inc.
Linkage analysis between manic‐depressive illness and 35 classical markers
Authors: Ewald Henrik , Mors Ole , Eiberg Hans
Published: June 2005

The present study used carefully established phenotypes, several methods to reduce misclassification, and conservative genetic parameters. For the 35 markers investigated no evidence of linkage to manic‐depressive illness was found, especially not to the markers on chromosomes 4q, 9q, and 19, which earlier has been suggested as possibly being linked to subtypes of manic‐depressive illness. Close linkage to FY and SS (GYPB) was excluded for all chosen phenotypic models and to ACP1 and ADA for broader phenotypic models. © 1994 Wiley‐Liss, Inc.
Genetic linkage mapping for a susceptibility locus to bipolar illness: Chromosomes 2,3,4,7,9,10p,11p,22, and Xpter
Authors: Detera‐Wadleigh Sevilla D. , Hsieh Wang‐Ting , Berrettini Wade H. , Goldin Lynn R. , Rollins Denise Y. , Muniec David , Grewal Raji , Guroff Juliet J. , Turner Gordon , Coffman Diane , Barrick J. , Mills Kate , Murray Jeffrey , Donohue Susan J. , Klein David C. , Sanders Jason , Nurnberger John I. , Gershon Elliot S.
Published: June 2005

We are conducting a genome search for a predisposing locus to bipolar (manicdepressive) illness by genotyping 21 moderate‐sized pedigrees. We report linkage data derived from screening marker loci on chromosomes 2, 3, 4, 7, 9, 10p, 11p, 22, and the pseudoautosomal region at Xpter. To analyze for linkage, two‐point marker to illness lod scores were calculated under a dominant model with either 85% or 50% maximum penetrance and a recessive model with 85% maximum penetrance, and two affection status models. Under the dominant high penetrance model the cumulative lod scores in the pedigree series were less than −2 at Θ = 0.01 in 134 of 142 loci examined, indicating that if the disease is genetically homogeneous linkage could be excluded in these marker regions. Similar results were obtained using the other genetic models. Heterogeneity analysis was conducted when indicated, but no evidence for linkage was found. In the course of mapping we found a positive total lod score greater than +3 at the D7S78 locus at Θ = 0.01 under a dominant, 50% penetrance model. The lod scores for additional markers within the D7S78 region failed to support the initial finding, implying that this was a spurious positive. Analysis with affected pedigree member method for COL1A2 and D7S78 showed no significance for linkage but for PLANH1, at the weighting functions f(p) = 1 and f(p) = 1/sqrt(p) borderline P values of 0.036 and 0.047 were obtained. We also detected new polymorphisms at the mineralocorticoid receptor (MLR) and calmodulin II (CALMII) genes. These genes were genetically mapped and under affection status model 2 and a dominant, high penetrance mode of transmission the lod scores of < −2 at Θ = 0.01 were found. © 1994 Wiley‐Liss, Inc.
Role of genetic factors in human sexual behavior based on studies of tourette syndrome and ADHD probands and their relatives
Authors: Comings David E.
Published: June 2005

Most significant variations in the expression of human sexuality are considered to be the result of learned behavior or psychological problems. Tourette syndrome (TS) is a common, hereditary tic and disinhibition disorder sometimes associated with compulsive use of obscene words (coprolalia) and previously reported to be occasionally associated with exhibitionism. To further explore the relationship between the Gts genes and sexual behavior, questions concerning a wide range of such behaviors were administered to 1,040 subjects, 14 years of age or older, consisting of 358 TS probands, 101 non‐proband relatives with TS, 359 non‐TS first degree relatives, 79 attention deficit hyperactivity disorder (ADHD) probands, 70 unaffected relatives of the ADHD probands, and 73 controls. The behaviors included magnitude of sex drive, sex orientation, exhibitionism, transvestitism, transsexualism, sadism, masochism, pedophilia, fetishism, aversion to being touched, and aversion to sex. While most of these behaviors occurred in a distinct minority of TS subjects, there was a significant positive correlation between each behavior examined and the degree of genetic loading for the Gts gene(s). The nature of these behaviors and their association with TS suggests many are variants of obsessive‐compulsive disorder. Studies in animals indicate that changes in serotonin and dopamine play a significant role in the sexual behavior and many lines of evidence are consistent with the hypothesis that TS is due to genetic changes in serotoun and dopamine metabolism. These studies suggest that genetic factors play a much greater role in a wide range of forms of sexual expression than previously thought. © 1994 Wiley‐Liss, Inc.
Clinical and biochemical analysis of two families with type I and type II mannosidosis
Authors: Bennet J. K. , Dembure P. P. , Elsas L. J.
Published: June 2005

We report on two unrelated patients with different presentations of mannosidosis. One patient was affected in early childhood with a severe phenotype characteristic of type I mannosidosis. The other was diagnosed with type II mannosidosis only after the onset of progressive neurologic deterioration in late adulthood. Both were detected by non‐invasive urinary screening of oligosaccharides. Lymphoblasts transformed from both patients' blood cells had markedly reduced lysosomal α‐mannosidase activity. Kinetic analyses showed that α‐mannosidase from the type I patient had a 400‐fold reduction in affinity while that from the type II patient was reduced 40‐fold. Lymphoblasts from all 4 parents had reduced α‐mannosidase activity, but there were overlapping activities among these type I and type II obligate heterozygotes. We conclude that screening urinary oligosaccharides will detect mannosidosis over a wide range of phenotypes, that lymphoblasts transformed from affected heterozygotes have decreased enzymatic activity, and that the severity of clinical expression is related to the degree of enzyme impairment. © 1995 Wiley‐Liss, Inc.
Duplication 3q syndrome: Molecular delineation of the critical region
Authors: Aqua Mfon S. , Rizzu Patrizia , Lindsay Elizabeth A. , Shaffer Lisa G. , Zackai Elaine H. , Overhauser Joan , Baldini Antonio
Published: June 2005

The phenotype of dup(3q) syndrome partially overlaps with Brachmann‐de Lange phenotype. Convulsions and eye, palate renal, and cardiac anomalies are more frequent in dup(3q) syndrome, while limb deficiencies, hirsutism, and synophrys are more characteristic of Brachmann‐de Lange syndrome. Whether the two syndromes have a biological relationship has yet to be demonstrated. Using two patient translocation cell lines, each involving distal 3q, we have narrowed the critical region of the dup(3q) syndrome to the interval 3q26.31–q27.3 and initiated its molecular characterization. We have mapped in this region 6 cosmid clones spanning approximately 3–5 Mb. The critical region appears to overlap with the region where a balanced translocation was found in a Brachmann‐de Lange patient. This work provides the mapping framework for finer molecular analysis of dup(3q) syndrome. © 1995 Wiley‐Liss, Inc.
“Balanced” karyotypes in six abnormal offspring of balanced reciprocal translocation normal carrier parents
Authors: Wenger Sharon L. , Steele Mark W. , Boone Leslie Y. , Lenkey Sharen G. , Cummins James H. , Chen Xiao‐Qing
Published: June 2005

Among 6800 consecutive blood samples studied for clinical cytogenetic diagnosis, we identified 30 families in which one parent of the proband had a balanced reciprocal autosomal translocation (excluding Robertsonian rearrangements). Twentyeight of the 30 families had a malformed and/or mentally retarded proband: 19 with an unbalanced derived chromosome, 3 with abnormalities involving chromosomes other than those in the translocation, 5 with a “balanced” reciprocal translocation, and 1 with a normal karyotype. We hypothesize that the latter 6 affected probands with “balanced” karyotypes could be abnormal due to submicroscopic deletions and duplications as was originally suggested by Jacobs [1984]. Particularly in these 6 families, 83% of translocation breakpoints were associated with fragile sites, more than expected by chance (P < 0.025). This supports the report of an association between fragile sites and constitutional chromosome breakpoints by Hecht and Hecht [1984]. To explain these findings, we propose that autosomal fragile sites are unstable areas which predispose to breaks and unequal crossing over near the fragile site breakpoints creating minute duplications and deletions. Consequently, newborn infants inheriting a seemingly “balanced” karyotype from a normal parent with a balanced reciprocal translocation may still be at an increased risk of being malformed and/or developmentally delayed because of submicroscopic chromosomal imbalances. © 1995 Wiley‐Liss, Inc.
Dandy‐Walker malformation in the Meckel syndrome
Authors: Summers Michael C. , Donnenfeld Alan E.
Published: June 2005

The Meckel syndrome (MS) is an autosomal recessive disorder classically defined by the triad of occipital encephalocele, multicystic kidneys, and polydactyly. Here we describe 3 sibs with varying manifestations of MS. The propositus had isolated cystic renal disease. The other sibs were both prenatally diagnosed with renal disease, polydactyly, and the Dandy‐Walker malformation, an unusual central nervous system defect in MS. These findings are discussed in the context of the phenotypic expression of MS and the nosology of this disorder and the cerebro‐reno‐digital (Meckel‐like) syndromes. © 1995 Wiley‐Liss, Inc.
Expression of SRY transcripts in preimplantation human embryos
Authors: Fiddler Morris , Abdel‐Rahman Burae , Rappolee Daniel A. , Pergament Eugene
Published: June 2005

We have examined the expression of SRY mRNA in individual in vitro fertilized preimplantation human embryos; because of ethical constraints, these studies were confined to embryos with one and three pronuclei. Using a sensitive reverse transcriptase‐polymerase chain reaction (RTPCR) assay, we observed SRY mRNA at the one‐cell through the blastula stages but not in spermatozoa. These results indicate that the de novo transcription of this sex‐specific gene occurs at a developmental time considerably earlier than that of gonadal differentiation. Our results also indicate that in vitro fertilized embryos with one pronucleus are likely to be diploid. © 1995 Wiley‐Liss, Inc.
Hereditary congenital posterior dislocation of radial heads
Authors: Reichenbach Herbert , Hörmann Dieter , Theile Herbert
Published: June 2005

We report on 4 patients with congenital posterior dislocation of radial heads in 3 generations of a family. Radiographs of the elbow joints of 3 individuals are presented. All affected subjects have mild limitation of extension and a strong restriction of rotation in the elbows. Comparison with previously described patients shows similarities in the X‐ray findings. Congenital posterior dislocation of the radial head can be unilateral or bilateral. This malformation is also found in patients with antecubital pterygium or nailpatella syndrome. This family confirms the autosomal dominant inheritance of congenital posterior dislocation of radial heads. © 1995 Wiley‐Liss, Inc.
Androgen receptor gene (CAG)n repeat analysis in the differential diagnosis between Kennedy disease and other motoneuron disorders
Authors: Ferlini A. , Patrosso M. C. , Guidetti D. , Merlini L. , Uncini A. , Ragno M. , Plasmati R. , Fini S. , Repetto M. , Vezzoni P. , Forabosco A.
Published: June 2005

An increase in the number of (CAG)n repeats in the first coding exon of the androgen receptor (AR) gene has been strongly associated with Kennedy disease (KD) (spinal and bulbar muscular atrophy). This is an X‐linked hereditary disorder characterized by motoneuron degeneration occurring in adults together with gynecomastia and hyperestrogenemia. We have performed AR gene molecular analysis in several members of a large family with KD as well as in 25 sporadic patients suffering from heterogeneous motoneuron disease (MND). An increase in the length of the (CAG)n repeats was detected, as expected, in all the affected males and in obligatory carrier females, some of which had minor signs of lower motoneuron involvement. There was only one possible exception, one young male with initial signs of the disease, who had an apparent normal length allele. An increased pathological allele was also found in 3 patients with MND. This indicates that the analysis of (CAG)n repeats of the AR gene plays a role in the differential diagnosis of this heterogeneous group of neurological diseases. © 1995 Wiley‐Liss, Inc.
Deletion of chromosome 2q24‐q31 causes characteristic digital anomalies: Case report and review
Authors: Boles Richard G. , Pober Barbara R. , Gibson Lisa H. , Willis Charla R. , McGrath James , Roberts Drucilla J. , Yang‐Feng Teresa L.
Published: June 2005

We describe a newborn boy with multiple anomalies, including bilateral split foot and an interstitial deletion of chromosome 2 (q24.2‐q31.1). Four additional cases in 2 families involving similar deletions have been reported. Bilateral digital anomalies of hands and feet were seen in all 5 cases, including a wide cleft between the first and second toes, wide halluces, brachysyndactyly of the toes, and camptodactyly of the fingers. Other common manifestations have included postnatal growth and mental retardation, microcephaly, down‐slanting palpebral fissures, micrognathia, and apparently low‐set ears. Bilateral digital anomalies were reported in 22 of 24 cases with deletions including at least part of region 2q24‐q31. Digital anomalies were not prevalent in 18 patients with deletions of chromosome 2q not overlapping 2q24‐q31. 2q31.1 appears to be the common deleted segment in all cases with significant digital anomalies, which implies the existence of one or more genes involved in distal limb morphogenesis in this region. HOXD13 and EVX2, located in the proximity of 2q31, were not deleted in our patient by Southern analysis.

Bilateral digital malformations of the hands and feet associated with other anomalies should be evaluated by chromosome analysis focused at the 2q24‐q31 region. © 1995 Wiley‐Liss, Inc.
Amelia of the arms and Femur/Fibula deficiency with splenogonadal fusion in a child born to a consanguineous couple
Authors: Lipson Anthony H.
Published: June 2005

A male infant was born with symmetrical tetramelic limb deficiency consisting of bilateral upper limb amelia with severe symmetrical proximal focal femoral deficiency and fibula deficiency associated with left splenogonodal fusion of the discontinuous type, micrognathia, and a prominent capillary haemangioma of the face. The parents are first cousin Lebanese muslims. This observation suggests the possibility of recessive inheritance in some cases of the Amelia, Femur‐Fibula dysostosis syndrome with or without splenogonadal fusion. © 1995 Wiley‐Liss, Inc.
Genital abnormalities in females with Bardet‐Biedl syndrome
Authors: Stoler Joan M. , Herrin John T. , Holmes Lewis B.
Published: June 2005

The major manifestations of the Bardet‐Biedl syndrome are digital anomalies, tapetoretinal degeneration, obesity, renal abnormalities, and hypogenitalism (described mainly in males). We report on 2 girls with Bardet‐Biedl syndrome who also had vaginal atresia. A similar association in females with Bardet‐Biedl syndrome was suggested in published reports of 11 affected individuals who had structural genital abnormalities, (some of which were missed in childhood), including persistent urogenital sinus, ectopic urethra, hypoplasia of the uterus, ovaries and fallopian tubes, uterus duplex, and septate vagina. The association of atresia of the vagina and other malformations of female genital structures in individuals with Bardet‐Biedl syndrome has often been missed in childhood and should be looked for more systematically. © 1995 Wiley‐Liss, Inc.