bluuebunny/crossref_metadata_2025 huggingface dataset:
Inbreeding effect on morbidity: II. Analyses of a third survey including and excluding infant‐juvenile mortality among Brazilian whites and Negroes
Authors: Elisbão T. , Freire‐Maia N.
Published: June 2005

Data on a survey involving 10,458 liveborn white and nonwhite (mulattoes and Negroes) persons have been analyzed to estimate B, A, and B/A for anomalies in general, both including and excluding infant‐juvenile mortality. In both instances and race groups, the approximate estimates of those parameters were 0.5, 4.5, and 12. Inbreeding seems to disclose a predominantly mutational load.
Inbreeding effect on morbidity: III. A review of the world literature
Authors: Freire‐Maia N. , Elisbão T. , Opitz John M.
Published: June 2005

A review of the international literature on the inbreeding effect on morbidity is presented. For anomalies in general, the estimates of B vary from 0.2 to 5.8, of A from 0.01 to 0.23, and of B/A from 3 to 77. The respective modal estimates are roughly around 0.5, 0.03, and 20. A review of the estimates for specific anomalies also shows a wide range of values: from B = 0.0008, A = 68 × 10−8, and B/A = 1,176 (for acheiropodia) to B = 2.9, A = 0.24, and B/A = 12 (for “incapacity for military service”). Some estimates of B/A lower than 12 have been obtained for congenital malformations in some countries. An overall analysis of the whole body of data suggests that most of the anomalies are either entirely or predominantly mutational in origin.
Effects of consanguineous marriages on morbidity and precocious mortality: Genetic counseling
Authors: Freire‐Maia Newton , Opitz John M.
Published: June 2005

The excess risks of morbidity and precocious mortality for the offspring of incestuous matings and of matings of uncles‐nieces and aunts‐nephews, first cousins, first cousins once removed, and second cousins have been estimated as 32%, 18%, 9%, 5%, and 2.5%, respectively. These estimates are based on the theory of Morton et al [1956], assuming a damage (genetic and nongenetic) of 20% for the offspring of nonconsanguineous couples and two “deleterious” equivalents per gamete. Other possibilities (a damage of 40%; 2.5 deleterious equivalents per gamete), a partition of the total risk into prenatal and postnatal events, and some aspects of the inbreeding theory are also presented. Comments intended for persons interested in counseling are provided.
Potential impact of a predictive test on the gene frequency of Huntington disease
Authors: Schoenfeld Miriam , Myers Richard H. , Berkman Barbara , Clark Eleanor
Published: June 2005

Fifty‐five individuals at 50% risk of inheriting Huntington disease (HD) were given in‐depth structured interviews to survey attitudes toward use of a predictive test and to assess the possible impact of such a test on the number of gene carriers born. Three‐quarters of the sample said they would take predictive test. Given a positive predictive or prenatal test, the number of individuals choosing to have children is reduced from 80% of the total sample to 42%, or by almost one‐half. The large proportion of at risk individuals who say they would use a predictive test underscores the importance of developing guidelines for its administration prior to implementation.
A bivariate problem in human genetics: Ascertainment of families through a correlated trait
Authors: Dawson Deborah V. , Elston Robert C. , Opitz John M.
Published: June 2005

In genetic analysis of pedigree data, nonrandom sampling occurs commonly and appropriate adjustments for the ascertainment procedure are necessary for the correct interpretation of results. In this paper we consider ascertainment models for the situation in which proband selection is made on the basis of one trait, but the desired object of analysis is another related trait for which the individuals in the pedigree also are measured. The ascertainment function corresponding to the most useful bivariate form, that involving two correlated quantitative traits, is described explicitly under suitable assumptions. As its form is mathematically intractable for purposes of pedigree analysis, an approximation is developed. Such ascertainment models accomplish corrections for ascertainment while permitting adjustment for covariates, analysis of traits correlated with the trait used in selection, and multivariate analysis of nonrandomly sampled pedigrees using linear combinations of traits.
Isoelectric focusing of serum in genetic counselling of families with cystic fibrosis
Authors: Super Maurice , Swindlehurst Christine
Published: June 2005

The high incidence of carriers of cystic fibrosis in the general population allows application of a less than perfect test to genetic counselling of relatives of children with the disorder and their spouses. In the absence of a definitive carrier detection test, we employ isoelectric focusing of serum in this way and include the a priori chance of carrier status in calculating the risk. The test will eventually be replaced but for the present is preferable in our hands to counselling based simply on the known gene frequency.
Constitutive fragile sites 1p31, 3p14, 6q26, and 16q23 and their use as controls for false‐negative results with the fragile(X)
Authors: Daniel Art , Ekblom Linda , Phillips Sandra , Opitz John M.
Published: June 2005

Fragile(X) estimations in fragile(X)‐mental retardation hemizygotes or heterozygotes can become falsely negative in stored blood (lymphocytes). This was shown in blood stored (before culture) at 4°C, room temperature (25°C), 37°C, and 39°C for 1–4 days. After storage, blood was cultured in Ham's F10‐5% FC serum with 0.1 μM FUdR and scored for fra(X) and the constitutive fragile sites at 3p14 and 6q26. It was found that the proportion of cells expressing the fragile(X) and the 3p14 site varied inversely with the temperature and time of storage. In addition, 50 patients and controls were scored for the three latter sites after routine 72–96‐hr culture in F 10–0.05 or 0.1 μM FUdR. The 3p14 site was detected in every individual tested in a mean ± S.D. of 11.3 ± 3.2% of cells (0.1 μM FUdR). It was found that this site was FUdR dose dependent whereas the 6q26 site was not. The 3p14 (but not the 6q26) site is therefore suitable as a control site for the FUdR effect. It is proposed that repeat studies are necessary when less then 4% 3p14 sites are present in specimens from males referred for fra(X) estimation. Other constitutive fragile sites (eg, 1p31 and 16q23) can also be used.
Apparent allelism of the hurler, scheie, and hurler/scheie syndromes
Authors: Mueller O. Thomas , Shows Thomas B. , Opitz John M. , Reynolds James F.
Published: June 2005

The Hurler, Scheie, and Hurler/Scheie syndromes are clinically distinct disorders due to inherited deficiencies of lysosomal α‐iduronidase activity. The genetic relationship of these disorders was investigated by complementation analysis using a heterokaryon enrichment procedure. Fusions between fibroblasts derived from Hurler, Scheie, or Hurler/Scheie subjects in any combination resulted in no detectable correction of α‐iduronidase activity, indicating that they form a single complementation group. Control fusions between these fibroblasts and mucolipidosis II or III cells, which are also α‐iduronidase deficient due to an enzyme processing defect, resulted in restoration of up to 57% of normal α‐iduronidase activity. These results also suggest allelism of the Hurler, Scheie, and Hurler/Scheie syndromes. However, the genetic make‐up of the Hurler/Scheie syndrome was not resolved.
Prenatal diagnosis of Meckel syndrome: Case reports and literature review
Authors: Johnson Virginia P. , Holzwarth David R. , Opitz John M. , Reynolds James F.
Published: June 2005

We report on 2 couples at risk to have Meckel syndrome (MS) offspring. Three pregnancies were monitored by ultrasonography and alpha‐fetoprotein (AFP) assay in midtrimester. Of the 2 involving an affected fetus, one was thought to be unaffected.

A literature survey was undertaken. Sources of error seem to lie in the heterogeneity of clinical manifestations and the variable onset and rate of progression of clinical components of MS and limitations in ultrasonographic resolution inherent in the scanner or due to the associated oligohydramnios.

The following observations/suggestions are made concerning the prenatal diagnosis of MS: 1) Utilize as many tests as are available. 2) Amniotic fluid AFP is more likely to show significant elevation than serum AFP. 3) Ultrasonography should concentrate on presence of oligohydramnios, small head diameter, cystic mass at the occiput, large kidneys, and absent bladder. 4) Use serial AFP and sonographic examination if findings are initially normal or equivocal.
Presumed homozygous Ehlers‐Danlos syndrome type I in a highly inbred kindred
Authors: Kozlova S. I. , Prytkov A. N. , Blinnikova O. E. , Sultanova F. A. , Bochkova D. N. , Opitz John M. , Reynolds James F.
Published: June 2005

While studying an extended family of individuals with the Ehlers‐Danlos (ED)syndrome type I, we found an affected male who was born to 2 affected consanguineous parents. This man had a more severe condition than that of his other affected relatives. Moreover, all 6 of his children were affected. Taking the pedigree data into account, the conditional probability of homozygosity for the ED gene in that patient was calculated as 97%. Some problems of the clinical and genetic approach to the recognition of the homozygous state in the ED syndrome are discussed using this family as an example.
A private view of heterozygosity: Eight‐year follow‐up study on carriers of the Tay‐Sachs gene detected by high school screening in montreal
Authors: Zeesman Susan , Clow Carol L. , Cartier Lola , Scriver Charles R. , Opitz John M. , Reynolds James F.
Published: June 2005

We surveyed 264 persons (132 carriers, 132 matched noncarriers) screened for Tay‐Sachs heterozygosity during 1974–76 in a program directed at senior high school students in Montreal. Among 198 who apparently received the questionnaire in 1982, the response rate was 42% (38 carriers, 45 noncarriers; age range 21–26 yr). Respondents and nonrespondents had no apparent demographic differences. Of eight unable to remember their genotype only one was a carrier (these persons were excluded from the study). The subjects were: single (75%), married (20%), engaged (3%), divorced (1%); 32% of carriers were engaged or married vs 16% of noncarriers. (There were no carrier couples in our sample, but one such couple, who married after being screened in the high school program, requested amniocentesis in 1981.) Only three of the 12 spouses or fiancé(s) of carriers have not been tested (vs 3 of 6 noncarrier partners). Only 19% of carriers now attach any “worry” to heterozygosity (vs 46% at the earlier time of test disclosure, P = 0.001); carriers with spouses or fiancé(e)s are less “worried” than unattached carriers. Only 3% of carriers claim they would change marriage plansif their fiancé(e) was also a carrier. Carriers and noncarriers uniformly approve (96%) genetic screening for themselves and for other mutant genotypes; 92% of carriers and 95% of noncarriers approve being screened in high school. These findings indicate that Canadians screened in high school: 1) have largely positive attitudes toward genetic screening long after the experience, and 2) are making appropriate use of the test result.
Neural tube defects in dup(11 q)
Authors: Bader P. I. , Haney S. M. , Munsick R. A. , Schubert S. R. , Hodes M. E.
Published: June 2005

We describe clinically and cytogenetically a fetus with multiple congenital anomalies and partial dup(11 q) born to a phenotypically normal mother with a 3:1 translocation. Fetal anomalies included complete cleft of lip and palate, small penis, myelomenigocele, and abnormal palmar creases. We think chromosome analysis should be performed when neural tube defects are observed in otherwise dysmorphic neonates, stillbirths, and abortuses.
Neural tube defects in Eastern Ontario and Western Quebec: Demography and family data
Authors: Hunter Alasdair G. W.
Published: June 2005

This paper reports the results of a study of families in the Eastern Ontario/Western Quebec region who had a child born with a neural tube defect during the years 1969–1981. As in several other geographic areas, the prevalence of neural tube defects at birth has fallen from previous levels. However, there was no evidence of further decline during the period of study. Socioeconomic and ethnic influences were noted, but there was no evidence of seasonal variation or any correlation with maternal age or parity. There was support for a causative role of maternal fever in some cases. The rates of miscarriage varied between pregnancies before and those after the proband, and there was an excess of males born prior to the proband. Family studies showed a 2.4% risk for sibs born after the proband and an excess of affected relatives on the maternal side. Knowledge of rates of occurrence in relatives is useful for counseling and the interpretation of the results of alpha‐fetoprotein screening.
The tricho‐rhino‐phalangeal syndrome with exostoses (or Langer‐Giedion syndrome): Four additional patients without mental retardation and review of the literature
Authors: Langer Leonard O. , Krassikoff Natalie , Laxova Renata , Scheer‐Williams Mary , Lutter Lowell D. , Gorlin Robert J. , Jennings Charles G. , Day Donald W.
Published: June 2005

We report on four patients with tricho‐rhino‐phalangeal syndrome with exostoses (TRPSE) who were not mentally retarded and review 32 previously published cases. These data enable more complete delination of the phenotype and document the variability of the clinical and radiographic manifestations. Information on the genetics and the association with del(8q) is discussed, as are management and avenues for further investigation. The apparent variability of intelligence in TRPSE patients together with the high incidence of other problems, including significant delay in speech development and hearing loss, make systematic multidisciplinary evaluation and long‐term treatment necessary to achieve the best outcome.
Maternal reproductive loss and cleft lip with or without cleft palate in human embryos
Authors: Shiota Kohei
Published: June 2005

Recognized spontaneous abortions in previous pregnancies were significantly more frequent in mothers of 87 Japanese embryos with cleft lip with or without cleft plate (CL(P)) than in mothers of normal embryos. The number of prior pregnancies was found to be smaller in mothers of CL(P) embryos with additional defects, suggesting that unrecognized abortions might also occur more frequently in these women. The higher incidence of abortions was associated with more severe forms of CL(P), ie, CL(P) with associated anomalies rather than isolated CL(P), and bilateral rather than unilateral CL. These results are compatible with the “multifactorial two‐threshold” model with a lower threshold beyond which the malformation occurs and a higher one beyond which the embryo dies. The present results are in contrast with the reduced spontaneous abortion rates in families of CL(P) probands reported previously. The reduced rates may be due to selection of those families in which CL(P) embryos escaped spontaneous abortion and survived to birth, although the effects of compensatory reproduction or maternal recall bias in postnatal data cannot be ruled out completely.
Fibrochondrogenesis: Lethal, autosomal recessive chondrodysplasia with distinctive cartilage histopathology
Authors: Whitley Chester B. , Langer Leonard O. , Ophoven Janice , Gilbert Enid F. , Gonzalez Claudette H. , Mammel Mark , Coleman Michael , Rosemberg Sergio , Rodriques Consuelo J. , Sibley Richard , Horton William A. , Opitz John M. , Gorlin Robert J.
Published: June 2005

Fibrochondrogenesis is a rare, neonatally lethal rhizomelic chondrodysplasia distinguished from other forms of lethal dwarfism by broad long‐bone metaphyses, pear‐shaped vertebral bodies, and by microscopic changes of cartilage with unique interwoven fibrous septa and fibroblastic dysplasia of chondrocytes. We report the second and third well‐documented cases of this apparently autosomal recessive disorder and discuss differential diagnosis.
Fibrochondrogenesis: Radiologic and histologic studies
Authors: Eteson Donna Jane , Adomian Gerald E. , Ornoy Asher , Koide Toshio , Sugiura Yasuo , Calabro Anna , Lungarotti Serena , Mastroiacovo Pierpaolo , Lachman Ralph S. , Rimoin David L.
Published: June 2005

Fibrochondrogenesis is a distinct, neonatally lethal, short‐limb skeletal dysplasia which was first described in a single patient in 1978. We report the radiographic and morphologic studies of 2 additional unrelated stillborn infants with fibrochondrogenesis. This syndrome has distinct radiographic and chondro‐osseous morphologic defects different from those seen in the other known skeletal dysplasias. The long bones are short and dumbbell‐shaped with metaphyseal flare. The spine is platyspondylic with superior‐inferior clefting defects, and the ribs are short and distally cupped. The growth‐plate cartilage is grossly disorganized and has a densely fibrous collagenous matrix when examined by light and electron microscopy. Light, transmission, and scanning electron microscopy shows diaphyseal and metaphyseal trabecular bone to be normal.
High‐resolution chromosome analysis: I. Applications and limitations
Authors: Schwartz Stuart , Palmer Catherine G.
Published: June 2005

High‐resolution chromosome preparations were examined in 55 couples experiencing multiple spontaneous abortions to determine if such studies might provide additional cytogenetic information. One translocation [46,XY, t(14;18)(q32;q22.2)] was detected that was not observed on routine metaphase preparations (GTG banding). In addition, an abnormality (not from the original sample) suspected on routine analysis was accurately identified as [46,XY, dir ins(12;21) (p12.3;q22.‐1q22.2)] only after high‐resolution studies. Metaphases with a total of 500–650 discernible bands per haploid set are most informative for high‐resolution analysis of a complete karyotype. Chromosomes yielding this number of bands demonstrate 6.7–14.2% homolog discordance and usually require only three to five karyotypes to reach a diagnosis. GTG proved more effective than RBG banding in conjunction with high‐resolution studies.
Linkage analysis in lattice corneal dystrophy
Authors: Kivlin J. D. , Lovrien E. W. , Maumenee I. H. , Bishop D. T. , Bias W.
Published: June 2005

Two kindreds of lattice corneal dystrophy (LCD) [McKusick, 1983, catalog No. 12220] were studied for linkage. Fifty‐one relatives were examined clinically, and 27 affected and 24 normal persons were ascertained. Tight linkage could be excluded for 15 informative markers with LOD scores of less than — 2.0. The largest positive LOD score was 0.56 at θ = 0.17 for linkage between haptoglobin and LCD. Combined with a previous study, the combined LOD score is 0.96.
The Potter sequence: A clinical analysis of 80 cases
Authors: Curry Cynthia J. R. , Jensen Karen , Holland Julie , Miller Linda , Hall Bryan D.
Published: June 2005

Eighty cases of Potter sequence due to a renal or urologic abnormality were studied retrospectively. The abnormal renal findings were bilateral renal agenesis in 21.25%; cystic dysplasia in 47.5%; obstructive uropathy in 25%; and others in 5.25%. Fifteen patients had multiple congenital anomalies; of these three had aneuploidy, four had autosomal recessive syndromes, and eight were of unknown cause. Results of chromosome analysis in 41 patients and 21 sets of parents were abnormal in three patients, one of whom had a balanced translocation carrier parent; two additional patients and three parents had apparently balanced translocations. There was one recurrence within the study (the first child had bilateral renal agenesis and the second cystic dysplasia). The ultrasound prenatal diagnosis of the renal abnormality was made in eight cases between 18 and 34 weeks. Family histories were suggestive of an autosomal dominant gene disorder with incomplete penetrance in four of 45 families with nosyndromic bilateral renal agenesis and cystic dysplasia. The evaluation of patients with the Potter sequence should include an examination for nonrenal defects, autopsy, chromosome analysis, and renal ultrasound or urologic evaluation of parents. Ultrasonographic prenatal monitoring of subsequent pregnancies in such families is strongly warranted because of a definite but unknown degree of recurrence risk.
Prenatal diagnosis of a severe deforming type of osteogenesis imperfecta
Authors: Aylsworth Arthur S. , Seeds John W. , Guilford W. Bonner , Burns Charles B. , Washburn David B.
Published: June 2005

A pregnancy at risk for a severe deforming type of osteogenesis imperfecta (OI) was monitored by ultrasonography and radiography. Long bone measurements were normal at 151/2 weeks gestation, but ultrasound detected an abnormality of one femur that appeared to be a fracture. The ultrasound study at 19 weeks revealed severe shortness of the femora, and radiographs showed only vertebral bodies with no other fetal skeletal parts clearly visible. These studies indicate the feasibility of prenatal diagnosis before 20 weeks for the more severe handicapping types of OI that are compatible with survival past the newborn period and that can result in death during later infancy.
Recurrence risk estimation of acute intermittent porphyria based on analysis of porphobilinogen deaminase activity: A Bayesian approach
Authors: Bonaïti‐Pellié C. , Phung L. , Nordmann Y.
Published: June 2005

Red cell porphobilnogen deaminase is known to be an indicator of the carrier state for acute intermittent porphyria (AIP). This enzyme was assayed in three groups of individuals at least 15 years old: 105 affected individuals or obligate carriers, 234 unaffected first‐degree relatives of patients, and 217 unrelated control persons. Analysis of the distribution of the control enzyme activities suggested presence of three commingled distributions. Also, the overlap between carrier‐group and control‐group values must be taken into account for genetic counseling of relatives whose enzyme activity lies within the overlap. A Bayesian approach is proposed to derive risks for these individuals, using the observed carrier and control distributions. The method is illustrated by deriving risks for a family from our sample.
Hyperpipecolic acidemia in neonatal adrenoleukodystrophy
Authors: Kelley Richard I. , Moser Hugo W.
Published: June 2005

Serum pipecolic acid was measured in patients with neonatal adrenoleukodystrophy (NALD), sex‐linked ALD, and the cerebrohepatorenal syndrome of Zell‐weger. Pipecolic acid was elevated, often markedly, in most of the patients with NALD but in none of those with X‐linked ALD or adrenomyeloneuropathy, or in normal adults and children, or children with cirrhosis of other neurodegenerative disorders.

The demonstration of elevated serum pipecolic acid in NALD adds to the previously recognized elevation of very‐long‐chain fatty acids (another Zellweger syndrome sign) and suggests that generalized peroxisomal dysfunction may be a characteristic of NALD as it appears to be of Zellweger syndrome, which diseases share some clinical characteristics. The nosologic significance of these findings is discussed.
Deletions of the long arm of chromosome 6: Two new cases and review of the literature
Authors: Young R. S. , Fidone G. S. , Reider‐Garcia P. A. , Hansen K. L. , McCombs J. L. , Moore C. M. , Opitz John M. , Reynolds James F.
Published: June 2005

Seven terminal deletions and four interstitial deletions of 6q have been reported. We present the clinical and cytogenetic findings of these cases and of two new patients with different interstitial deletions of 6q. Although there are too few cases of interstitial deletions to identify one or more clinical syndromes associated with monosomies of the more proximal regions of 6q, a terminal 6q deletion syndrome is proposed. Its major components are microcephaly with mental retardation, strabismus, apparently low‐set malformed ears, a broad nasal bridge, micrognathia, apparently short neck, congenital heart defect, abnormal palmar creases, and various hand abnormalities.
Hairbulb tyrosinase activity in oculocutaneous albinism: Suggestions for pathway control and block location
Authors: King Richard A. , Olds David P. , Opitz John M. , Reynolds James F.
Published: June 2005

Hairbulb tyrosinase activity was determined in 72 individuals with five types of oculocutaneous albinism (OCA) and 64 obligate heterozygotes. Type IA (tyrosinase‐negative) and type IB (yellow mutant) individuals had low or no measurable tyrosinase activity, and heterozygotes for these two types could be detected with this assay. Type II (tyrosinase‐positive) individuals had moderate to high activity, and the heterozygotes for this type could not be detected. Type III (minimal pigment) individuals had low activity, and heterozygote levels were useful in detecting this type of OCA. Type VI (Hermansky‐Pudlak syndrome) individuals had moderate to no measurable activity, and heterozygotes for this type could not be detected. The implication of the tyrosinase assay results in light of the phenotype and the possible location of the pigment block in these forms of OCA are discussed.
Genetic epidemiology of twinning: A population‐based study
Authors: Philippe P. , Opitz John M. , Reynolds James F.
Published: June 2005

We report on kinship analysis of mothers with twins and a study of their ancestors and inbreeding. A pair‐matched case‐control design supports the analyses. Nearly as high a number of ancestors was found at the origin of cases as in control individuals. Study cases were less inbred than control subjects, but their kinship was higher, especially for unlike‐sex twins born after age 30 years. The results indicate a genetic origin of both types of twins and possibly a highly spread gene with dominant or co‐dominant expression.
Duplication of hands and feet, multiple joint dislocations, absence of corpus callosum and hypsarrhythmia: Acrocallosal syndrome?
Authors: Sanchis Amparo , Cerveró Luís , Martínez Antonio , Valverde Carlos , Opitz John M. , Reynolds James F.
Published: June 2005

We describe a 14‐month‐old female infant with absence of corpus callosum, atrophy of optic nerve, peculiar face, complex polydactyly, multiple joint abnormalities, and femoral shortness. The similarities to and differences from previously reported cases of this kind suggest that our patient has a new type of acrocallosal syndrome.
Red blood cell adenine nucleotides abnormalities in down syndrome
Authors: Stocchi Vilberto , Magnani Mauro , Cucchiarini Luigi , Novelli Giuseppe , Dallapiccola Bruno , Opitz John M. , Reynolds James F.
Published: June 2005

The red blood cell adenine nucleotides of 20 Down Syndrome patients and 20 healthy controls were determined by a new high‐performance liquid chromatography method. All patients showed increased concentrations of adenosine 5′‐diphosphate (ADP) and adenosine 5′‐monophosphate (AMP), while adenosine 5′‐triphosphate (ATP), nicotinamide adenine dinucleotide (NAD+) and nicotinamide adenine dinucleotide phosphate (NADP+) were within normal ranges. This alteration of the energetic charge could be partly responsible for the impairment of glucose metabolism in these patients.
Multicore disease in sibs with severe mental retardation, short stature, facial anomalies, hypoplasia of the pituitary fossa, and hypogonadotrophic hypogonadism
Authors: Chudley Albert E. , Rozdilsky Bohdan , Houston C. Stuart , Becker Lawrence E. , Knoll Joan H. , Opitz John M. , Reynolds James F.
Published: June 2005

We describe a family in which two adult sibs presented with a history of congenital nonprogressive myopathy, severe mental retardation and evidence of mild generalized weakness, short stature, musculoskeletal deformities, facial anomalies, sexual infantilism, and radiologic evidence of pituitary hypoplasia. The parents were first cousins. An excess of other, apparently unrelated, genetic conditions were present in other family members. Results of histochemical and electron microscopy studies of muscle biopsies from both affected individuals were compatible with multicore disease. This newly described syndrome likely is an autosomal recessive trait and appears to be the first reported association of multicore disease with mental retardation.
Deletions of the long arm of chromosome 10
Authors: Shapiro Steven D. , Hansen Kathryn L. , Pasztor Linda M. , DiLiberti John H. , Jorgenson Ronald J. , Young Robert S. , Moore Charleen M. , Opitz John M. , Reynolds James F.
Published: June 2005

Patients with a partial deletion of the long arm of chromosome 10 are rare. We report eight new cases involving various segments of 10q: one terminal deletion (10q26), four (8;10) translocations resulting in terminal deletions (10q26) and duplications (8q24:3), a de novo interstitial deletion (10q23), an interstitial deletion due to a (10;13) translocation (10q11.2 → 10q22.1), and a ring (10p15 → 10q26).
Distichiasis, congenital heart defects and mixed peripheral vascular anomalies
Authors: Goldstein Stanley , Qazi Qutub H. , Fitzgerald Joseph , Goldstein Joseph , Friedman Anita P. , Sawyer Philip , Opitz John M. , Reynolds James F.
Published: June 2005

We report on a previously apparently unreported syndrome of distichiasis with congenital heart defects and with mixed peripheral vascular anomalies in a mother and her four children. The mother had a ventricular septal defect; both daughters had surgery for patent ductus arteriosus. Sinus bradycardia alone (elder son), with stress induced asystole (younger son), and with wandering atrial pacemaker (both daughters) are documented electrocardiographically. Three of the five have edema, two have visible varicosities, three have symptoms consistent with chronic venous disease of the legs, and the older daughter has complaints consistent with arterial disease in the legs. Doppler flow studies demonstrated post‐phlebitic syndrome in all but the younger daughter, and vasospastic disease in the mother, older daughter, and second son.
Familial spinocerebellar degeneration with corneal dystrophy
Authors: Kaloustian Vazken M. Der , Jarudi Nabil I. , Khoury Muin J. , Afifi Adel K. , Bahuth Nadia B. , Deeb Mary E. , Shammas John , Mikati Muhammad A. , Opitz John M. , Reynolds James F.
Published: June 2005

We report on two sisters born to normal but consanguineous parents, with the unusual combination of spinocerebellar degeneration and corneal dystrophy. Their manifestations include mental subnormality, bilateral corneal opacification starting in the second year of life and leading to severe visual impairment, and slowly progressive cerebellar abnormalities with variable dorsal column and upper motor neuron involvement. A third sister had only minor spinocerebellar signs but no eye findings, and three other sibs were completely normal. Both affected sisters underwent penetrating keratoplasty and their vision improved. Histologic examination showed findings of corneal dystrophy including corneal edema, thickening of Descement membrane, and degenerative pannus. High‐resolution light and electron microscopy of muscle and sural nerve performed on both patients was abnormal. It is suggested that, in this family, the corneal dystrophy and spinocerebellar degeneration are pleiotropic manifestations of an autosomal‐recessive disorder.
The centralized prenatal genetics screening program of New York City III: The first 7,000 cases
Authors: Benn Peter A. , Hsu Lillian Y. F. , Carlson Ann , Tannenbaum Hody L. , Opitz John M. , Reynolds James F.
Published: June 2005

The Prenatal Diagnosis Laboratory of New York City (PDL) is a regional program for the prevention of genetic diseases. The administrative aspects of the establishment of the laboratory were described in papers I [Hsu, 1981] and II [Hsu and Benn, 1981] in this series. We now report our experience of the first 7,000 referrals to the laboratory.

The laboratory achieved a success rate of 99.5% in obtaining a diagnosis. The frequency with which a repeat amniocentesis was required was 1.9%, usually attributable to inadequate initial amniotic fluid volume or condition. Cases were completed in an average time of 20.82 days.

A total of 149 (2.13%) cytogenetic abnormalities were detected. There were 59 nonmosaic autosomal trisomies and 29 sex chromosome abnormalities. The incidence of unbalanced structural abnormalities (0.186%) was much higher than that reported in surveys of newborn infants largely because of the prenatal detection of cases with supernumerary chromosomes. The incidence of balanced structural abnormalities was also considerably higher than that found in surveys of the newborn population, in part because of the detection of subtle familial pericentric inversions of common chromosome regions (inv Y)(p11q11), inv(2)(p11q13), and inv(1)(p11q13). The incidence of cases with multiple independent chromosome abnormalities was no higher than expected by chance. A high incidence of mosaicism, pseudomosaicism, and maternal cell contamination was found. Screening for neural tube defects accounted for the detection of a further 16 abnormalities.

Nearly all women with severely abnormal fetuses (trisomy 13, 18, 21) elected to terminate their pregnancy whereas only 62% of patients with a prenatally.
In vivo alteration of a mutant human protein using the free thiol cysteamine
Authors: Gahl William A. , Gregg Richard E. , Hoeg Jeffrey M. , Fisher Edward
Published: June 2005

Inborn errors of metabolism in which there is a mutant protein due to a cysteine for arginine substitution may be evidence for this derives from patients with type III hyperlipoproteinemia, who are homozygous for apolipoprotein E2, which differs in charge and in vitro function basedon a single such amino acid substitution. The plasma of a type III hyperlipoproteinemic patient, when made at least 50m with respect to cysteamine in vitro, demonstrated a charge shift of the apolipoprotein E isoelectric focusing pattern from the E2 to the normal E3 and E4 positions. Two Children treated for cystinosis with cysteamine each exhibted some charge alteration of their apoE3 to a form migrating in the apoE4 position. The use of thiol reagents such as cysteamine to specifically alter selected mutant human proteins, such as antithrombin III Toyama, may be added to our therapeutic armamentarium in the treatment of life‐threatening metabolic disorders.
An unusual distal arthrogryposis
Authors: Kawira Esther Lehman , Bender Harvey A. , Opitz John M. , Reynolds James F.
Published: June 2005

We report on a mother and her dizygotic twin fetuses who were affected with distal arthrogryposis. In addition the mother has cervical vertebral anomalies, scoliosis, short stature, nuchal and axillary pterygia, and unusual facial appearance. The fetuses had a short neck, pterygium colli, retrognathia, and mild apparent scoliosis. We think that these three individuals have a previously undescribed type of distal arthrogryposis.
Hypergonadotropic hypogonadism with congestive cardiomyopathy: An autosomal‐recessive disorder?
Authors: Malouf Joe , Alam Samir , Kanj Hassan , Mufarrij Amjad , Der Kaloustian Vazken M.
Published: June 2005

We report on two sisters with ovarian dysgenesis and secondary hypergonadotropic hypogonadism and congestive cardiomyopathy. Their parents are first cousins. It is suggested that these are the main manifestations of a previously unreported autosomal‐recessive syndrome.
A thermolabile variant of α‐L‐fucosidase—clinical and laboratory findings
Authors: Blitzer Miriam G. , Sutton Millicent , Miller James B. , Shapira Emmanuel , Opitz John M. , Reynolds James F.
Published: June 2005

A family with two sibs affected clinically with the severe infantile form of fucosidosis is described. Biochemical studies revealed a relatively high residual activity (34–60% of normal) with markedly decreased thermostability. The importance of including thin layer chromatography for urinary oligosaccharides in the diagnostic workup for such patients is emphasized.
Vesicoureteric reflux: Segregation analysis
Authors: Chapman C. J. , Bailey R. R. , Janus E. D. , Abbott G. D. , Lynn K. L. , Opitz John M. , Reynolds James F.
Published: June 2005

Complex segregation analysis was applied to data from 88 families containing at least one person with vesicoureteric reflux. Analysis showed that a single major locus was the most important causal factor in this condition, with the mutant allele being dominant to the normal allele and having a gene frequency of about 0.16% Forty‐five percent of gene carriers will have vesicoureteric reflux and/or reflux nephropathy as adults and 15% will develop renal failure, compared to 0.05% and 0.001%, respectively, for those not carrying the gene. This analysis confirms the importance of screening close relatives of persons with proven vesicoureteric reflux or reflux nephropathy.
Anomalies associated with cleft lip, cleft palate, or both
Authors: Shprintzen Robert J. , Siegel‐Sadewitz Vicki L. , Amato John , Goldberg Rosalie B. , Opitz John M. , Reynolds James F.
Published: June 2005

Numerous investigators have reported on a low frequency of other anomalies in patients with cleft lip, cleft palate, or both. The data have been somewhat inconsistent, ranging from a 3% to over 30% frequency of associated malformations. However, a recent study concluded that over half of the children with clefts at a large metropolitan center have associated anomalies. In an effort to elucidate further the genetic and morphologic characteristics of patients with clefts, 1,000 patients with clefts of the lip, palate, or both were examined and reviewed. The results indicate that associated anomalies occur in 63.4% of the sample. Approximately half of the patients with multiple anomalies have recognized syndromes, sequences, or associations, while the other half have physical examination (apparently one‐of‐a‐kind) syndromes. The high frequency of associated anomalies has obvious implications for the genetic counseling offered to all patients at cleft palate and craniofacial centers. The frequency of associated anomalies also raises questions regarding the validity of past genetic research involving populations of subjects with clefts.
Familial microcephaly with normal intelligence, immunodeficiency, and risk for lymphoreticular malignancies: A new autosomal recessive disorder
Authors: Seemanová Eva , Passarge E. , Beneškova Dagmar , Houštěk J. , Kasal P. , Ševčìková Melanie , Opitz John M. , Reynolds James F.
Published: June 2005

We describe nine patients with an apparently new genetic disorder characterized by: 1 (microcephaly with normal intelligence; 2) “bird”‐like facial appearance; 3( cellular and humoral immune defects; and 4) increased risk for lymphoreticular malignancies. The postmortem findings of five patients are described. Chromosome instability appears not to be a component of the disorder. The occurrence in three pairs of sibs and isonomy in another family suggests autosomal recessive inheritance.
The effect of Mendelian disease on human health: A measurement
Authors: Costa Teresa , Scriver Charles R. , Childs Barton , Opitz John M. , Reynolds James F.
Published: June 2005

We describe an attempt to measure effects of Mendelian phenotypes on human health (homeostasis) in man. We used the McKusick Catalogs as the source for descriptions of autosomal dominant, recessive, and X‐linked phenotypes. Three hundred and fifty one entries (76% of the initial sample) were disadaptive causing an impairment, disability, or handicap. (Terms used are in accordance with World Health Organization (WHO) definitions.) Phenotypic effects were scored to measure impact on life‐span, reproductive capability, and psychosocial characteristics. We found 1) 25% of the disadaptive Mendelian phenotypes were apparent at birth and over 90% by the end of puberty; age at onset is unimodal in distribution for autosomal recessive and X‐linked diseases, and trimodal for autosomal dominant (with modes during morphogenesis, infancy, and early adult life); 2) 58% of phenotypes involved more than one anatomical or functional system; autosomal dominants were more likely to involve only a single system; 3) life‐span was reduced in 57%, particularly in those with onset in pre‐ or intra‐reproductive life, and more often in recessive and X‐linked diseases (data corrected for genetic lethals); prognosis varied with system involvement; 4) reproductive capability was impaired in 69% of phenotypes; and 5) most phenotypes compatible with life beyond infancy caused psychosocial handicap and limited the access to schooling and work. These findings have implications for medical care.
The effect of Mendelian disease on human health. II: Response to treatment
Authors: Hayes Ailish , Costa Teresa , Scriver Charles R. , Childs Barton , Opitz John M. , Reynolds James F.
Published: June 2005

We describe an attempt to measure efficacy of treatment in the Mendelian diseases of man. We used the McKusick Catalogs to identify 351 single gene diseases. We scored the impact of each disease in seven phenotypic categories: lifespan, reproductive capability, somatic growth, intellectual development, learning ability, capacity to work, and cosmetic effect. We then scored the success of treatment in ameliorating each of these component manifestations separately and together. The response to treatment was slight in the whole sample (n = 351): lifespan was increased in 15%, reproductive capability in 11%, and social adaptation in 6%. We observed that the mutant gene product was known in only 15% of the conditions comprising our sample. Since the mutant polypeptide is known in most inborn errors of metabolism, the diseases of this type (n = 65) in our sample of Mendelian traits were studied separately. In each of the seven categories of phenotypic impact, only a few of the hereditary metabolic diseases responded in any degreee to specific treatment: the treatment gave complete relief in 12%, there was a partial response in 40%, and none in the remaining 48%. These findings have implications for prognosis, genetic counseling, and medical care of patients with Mendelian disease.
Paternity testing with genetic markers: Are Y‐linked genes more efficient than autosomal ones?
Authors: Chakraborty Ranajit , Opitz John M. , Reynolds James F.
Published: June 2005

The average probability of exclusion for a Y‐linked locus is computed and compared with that for an autosomal locus. It is shown that even if a Y‐linked locus is only marginally polymorphic, it considerably enhances the chance of paternity exclusion in paternity dispute cases involving sons. For the positive identification of paternity, a Y‐linked marker is not necessarily more ideal than an analogous autosomal marker since the discrimination of true fathers from random men not excluded from paternity (RMNEP) is still difficult on the basis of a paternity index. It is concluded that Y‐linked markers are more efficient for paternity exclusions of male children, while for the positive identification of paternity their advantages over the autosomal markers are questionable.
Anthropometric discrimination among affected, at‐risk, and not‐at‐risk individuals in families with Huntington disease
Authors: Farrer Lindsay A. , Yu Pao‐Io , Opitz John M. , Reynolds James F.
Published: June 2005

An earlier report showed significant differences among Huntington disease (HD) patients, controls, and particular age cohorts of at‐risk persons for several dimensions of body mass and for several linear and craniofacial components of the body. In this investigation a function was derived from a stepwise discriminant analysis of the affected and unaffected groups, and used to classify the at‐risk individuals according to HD gene carrier status. The function, comprised of body mass index, subscapular skinfold, head length, and sitting height, classified 95% of the controls and 87% of the affected individuals correctly. Approximately 80% of the individuals at‐risk were classified with 80% or greater certainty.

We propose that anthropometric variables may prove to be a powerful tool for basic research in HD and the derived discriminant function has potential clinical value as a diagnostic and preclinical diagnostic aid. We emphasize that corroborative testing on other sample populations of HD families is required before these techniques are utilized. Also, it is imperative that the anthropometric protocol include appropriate standardization of the raw measurement data.
A method to assess the environment for genetic studies: The common environment index and the household relationships interview
Authors: Hunter Saundra MacD , Rosenbaum Peter A. , Borecki Ingrid B. , Elston Robert C. , Berenson Gerald S. , Opitz John M. , Reynolds James F.
Published: June 2005

Genetic and environmental influences in causing a disease are difficult to measure because of lack of precision in identification of relevant nongenetic variables.

The Household Relationships Interview and Schedule was developed to measure shared common environment in families (Common Environment Index) and to take into account developmental stages throughout the life cycle and separation/ disruption. Seven trained persons interviewed three individuals who reported fictitious interrelated life histories varying in length and complexity. Discrepancies between the recorded data and the true data were analyzed. Overall 96.1% of the items were recorded correctly. Thus, the method has shown good face and construct validity and reliability for measuring quantity of time shared by relatives in a common household. Common environment as measured by this instrument should be a particularly useful tool in behavior–genetic studies.
Enhanced expression of chromosome fragile site 10q25 in chronic myelogenous leukemia
Authors: Morgan Rodman , Morgan Stephanie S. , Hecht Frederick , Opitz John M. , Reynolds James F.
Published: June 2005

Spontaneous expression of a BrdU‐sensitive fragile site at 10q25 was observed in normal lymphocytes and malignant blood and bone marrow cells in chronic myelogenous leukemia (CML). The cells were marked by a Philadelphia chromosome rearrangement due to insertion of 22q11 → q13 at 11q13. The fragile site at 10q25 was expressed in larger proportions of malignant than normal cells. Although this fragile site is not at a cancer chromosome breakpoint, malignancy enhanced its expression, consistent with a cascade effect.
The heterogeneity problem. I: Separating genetic from environmental forms of the same disease
Authors: Greenberg David A. , Hodge Susan E. , Opitz John M. , Reynolds James F.
Published: June 2005

The purposes of this work were 1) to reparameterize the likelihood used in segregation analysis in a way particularly suited to detecting heterogeneity (the result of the analysis is a parameter giving the proportion of families with the genetic form of the disease in the dataset) and 2) to test how well this reparameterization works using simulation.

We assume that a dataset contains nuclear family data, with some of the families having a form of the disease that is environmentally caused and the others with a genetic form of the disease. In this study, we considered the case where the genetic form is a simple recessive and the environmental form a random model. The underlying parameters were the gene frequency, q, and the frequency of sporadics, R. We reparameterized the likelihood in terms of α, the percentage of genetic families in the dataset, which we attempt to estimate. We contrast the estimates of α with the population heterogeneity as reflected in the estimates of q and R.

For the simulation, nuclear families are generated. Genetic families were simulated with a mendelian recessive pattern and environmental families according to a simple random model.

Over a wide range of generating parameters, estimates of α were good, differing from the “true” values by only a few percent. Estimates of q and R, on the other hand, ranged from fair to poor. Our results indicate that the amount of heterogeneity in a dataset can be accurately estimated using segregation analysis, even when estimates of the gene frequency and penetrance among sporadics are unreliable.