A study of fluctuating dermatoglyphic asymmetry in the sibs and parents of cleft lip propositi.

Fluctuating asymmetry was studied in cleft lip propositi and their normal sibs and parents. The traits examined were a-b ridge counts and fingerprint patterns. Propositi with a family history of this congenital malformation and their normal sibs and parents were significantly different from the controls for this type of asymmetry. Propositi without a family history and their normal sibs and parents were similar to the controls. These results support the hypothesis that familial and sporadic cases of congenital cleft lip are different entities and give evidence for a genetic mechanism in the parents and sibs of the familial cases that may account for this congenital disorder and, concomitantly, increased fluctuating asymmetry.     

Velopharyngeal variations in relatives of cleft-affected individuals

Eighteen families each with two or more cleft lip and palate patients were studied by speech cephalometry for evidence of velopharyngeal inadequacy (VPI). With this total of 56 persons, three groups were recognized: 1) patients with cleft lip only (N = 7), 2) unaffected sibs of CL(P) probands and the unaffected parents with the positive clefting history on their side of the family (N = 33), and 3) unaffected parents with negative CL(P) history to their side of the family (N = 16). The latter served as controls. The velopharyngeal mechanism in function was evaluated by voicing the fricative/S/. The results showed no significant differences in the length of either the resting soft palate or pharyngeal depth among the three groups. Even though a significant (P less than 0.01) increase in soft palate length while voicing /S/ was found in group 2 relatives compared to group 3 controls, the failure to find differences in either resting palate length or pharyngeal depth coupled with a failure to demonstrate VPI in group 2 subjects by speech testing leaves the value of this observation uncertain.     

Cytogenetic investigations in families with ataxia-telangiectasia.

Chromosomal studies were performed on peripheral blood lymphocytes and cultured skin fibroblasts from five Israeli-Moroccan families with ataxia-telangiectasia. A total of 24 individuals, including seven propositi, was investigated. Among the probands, significantly elevated rates of chromosome damage were observed in both blood and skin. Skin fibroblasts of affected individuals showed several orders of magnitude more chromosome breakage than lymphocytes. Increased rates of chromosome damage were also observed in the fibroblasts of some phenotypically normal family members (obligate heterozygotes and sibs) when compared to normal controls. An apparent abnormal clone of cells, possessing a large acrocentric marker chromosome (14q+), was observed in varying proportions among cells of all the propositi (2-5% of lymphocytes; 1-9% of fibroblasts).     

A familial tetraphocomelia syndrome involving limb deformities,cleft lip,cleft palate,and associated anomalies —A new syndrome

Summary This paper reports a rare malformation syndrome which is observed in two sibs (brother and sister) of a family. It consists of nearly symmetric reductive defects of the limbs, flexon contractures of various joints, cleft lip and cleft palate, multiple minor abnormalities including capillary hemangioma of the forehead, hypoplastic cartilages of ears and nose, micrognathia, intrauterine growth retardation, and possibly mental retardation. Chromosomes of both parents and propositi are normal. Genetic data suggest autosomal recessive inheritance.     

Are oral clefts a consequence of maternal hormone imbalance? evidence from the sex ratios of sibs of probands

BACKGROUND: The causes of oral clefts (cleft lip with or without cleft palate, CL/P, and cleft palate alone, CP) have not been established. However, maternal intrauterine hormone profiles have been suspected of being involved. There is now substantial evidence that maternal hormone concentrations around the time of conception partially control the sexes of offspring. It is possible that the hormone profiles that control sex of offspring share features of the profiles suspected of causing clefts. This can be tested by examining the sex ratios (proportions male) of the unaffected sibs of probands. If these sex ratios are skewed in the same direction as that of probands, that suggests, ex hypothesi, maternal hormonal involvement in the causation of clefts. METHODS: Accordingly, a search was made for data on the sex ratios of the unaffected sibs of probands with clefts. For reasons given in the text, this search was informal rather than based on electronic data retrieval systems. Nine papers were located giving sex ratios of sibs of probands with CL/P and CP. RESULTS: Published data suggest that the sibs of probands with CL/P have a significantly higher sex ratio than the sibs of probands with CP. Thus the sib sex ratios are skewed in the same direction as those of the probands themselves. In other words, parents (mothers) of CL/P patients apparently have a tendency to produce boys, and parents of CP patients to produce girls. CONCLUSION: Accordingly, it is suggested that maternal hormone profiles may partially explain the unusual sex ratios (of probands and their sibs), as well as the malformations.     

A family study in transposition of the great vessels and in tricuspid atresia

Summary A group of 186 propositi with transposition of the great vessels (TGV) and 33 propositi with tricuspid atresia (TA) were studied. Data were obtained from hospital records and complemented by questionnaires and in part by personal interview and clinical examination. The main results were among sibs of propositi with TGV an increased incidence of TGV (0.0135±0.0054) and of congenital heart disease in general (0.0495±0.0103) (K=0, r_min=1). Among 92 sibs of propositi with TA only one with patent ductus arteriosus was found. The sex ratio of the propositi with TGV was 1.95. There was also noted a highly abnormal sex ratio among sibs of parents of patients with TGV in part confirming the findings of Knox.A male excess was found in paternal and maternal sibships and was also present in sibships of propositi. Data about seasonal distribution were inconclusive as were data about consanguinity of parents. No parental age or birth order effect was found in either group.This work has been carried out in part during the author's stay at the Genetic Clinic of the Children's Memorial Hospital, Dept. of Pediatrics, Northwestern University Medical School (Prof. D. Y.-Y. Hsia, M.D.). Data have been collected in collaboration with Dr. M. H. Paul, director of the Dept. of Cardiology of the Children's Memorial Hospital, Willis J. Potts Children's Heart Center. The author was supported in part by a grant from the US Public Health Service, National Institutes of Health and a Fulbright Travel Grant.     

Maternal effects in human cleft lip and palate.

To look for a persistent maternal effect of CL(P) and CP, 8,000 pedigrees were screened for half sibships, and data were pooled from 16 investigators. After excluding known genetic or cytogenetic diagnoses from the probands with facial clefts, a recurrence risk of .011 was obtained for CL(P) based upon 342 maternal half sibs. This was nearly identical to the risk of .014 based upon 210 paternal half sibs. CP proband frequencies of .004 for maternal half sibs and .009 for the paternal counterparts were also found. The lack of significant maternal effects in this data supports previously reported data from twin studies and from interracial crosses from Hawaii. The lack of maternal effect in human CL(P) and CP is in contrast to genetic data on clefting in mice.     

Refsum's disease (heredopathia atactica polyneuritiformis)

The formal genetics of 37 patients suffering from Refsum's disease is reviewed. The absence of the disease in parents and relatives excepts sibs of the propositi, the high parental consanguinity rate, and the observed number of affected sibs are in agreement with the assumption of an inheritance by a rare autosomal recessive gene. The geographical distribution of the patients suggests that most of them may have originated from one Scandinavian stock.     

Genetics of cleft lip and cleft palate in China.

During the past 10 years, 60 cases of cleft lip with or without cleft palate [CL(P)] were recorded among 45,072 newborns at Shanghai International Peace Maternity and Infant Hospital, China. The incidence was 1.33 per 1,000 births. The family histories of 163 CL(P) patients were analyzed. The incidences of CL(P) in the first-, second-, and third-degree relatives of CL(P) patients were 11/246 (4.47%), 10/1,032 (0.97%), and 6/1,727 (0.35%), respectively. Of the 163 probands, three had a history of consanguinity of the parents (1.8%), in contrast to 0.77% in the general population. These data are suggestive of multifactorial inheritance. The heritability of CL(P) in our study calculated by Falconer's formula was 77.6%.     

Congenital defects of the upper lateral incisors (ULI): Condition and measurements of the other teeth,measurements of the superior arch,head and face

We surveyed a French male population for the incidence of missing or reduced upper lateral incisors (ULI). In 5,738 subjects, we observed an incidence of 1.59% with one or two reduced ULI (the other normal) and 1.90% with one or two missing ULI (the other normal or reduced), altogether, 3.49% affected subjects. Furthermore, 250 random controls were observed. Agenesis of other teeth is more frequent in propositi. Missing third molars were 12.4% in controls, 24.0% in propositi with reduced ULI and 39.6% in propositi with two missing ULI. Furthermore, agenesis of incisors, canines and premolars ranges from 0.4% in controls to 1.3% in propositi having reduced ULI and 5.0% in propositi with two missing ULI. So, propositi with reduced ULI are intermediate between the controls and the propositi with missing ULI with respect to the frequency of agenesis of other teeth. On the other hand, a different ranking is observed with respect to the teeth measurements: reduction of tooth size is more marked in propositi with reduced ULI than in propositi with missing ULI. The reduction mainly affects canines, incisors and to a lesser degree, premolars. Arch length and interpremolar diameters are smaller in propositi with missing ULI, compared with controls.     

Use of parents, sibs, and unrelated controls for detection of associations between genetic markers and disease.

Detecting the association between genetic markers and complex diseases can be a critical first step toward identification of the genetic basis of disease. Misleading associations can be avoided by choosing as controls the parents of diseased cases, but the availability of parents often limits this design to early-onset disease. Alternatively, sib controls offer a valid design. A general multivariate score statistic is presented, to detect the association between a multiallelic genetic marker locus and affection status; this general approach is applicable to designs that use parents as controls, sibs as controls, or even unrelated controls whose genotypes do not fit Hardy-Weinberg proportions or that pool any combination of these different designs. The benefit of this multivariate score statistic is that it will tend to be the most powerful method when multiple marker alleles are associated with affection status. To plan these types of studies, we present methods to compute sample size and power, allowing for varying sibship sizes, ascertainment criteria, and genetic models of risk. The results indicate that sib controls have less power than parental controls and that the power of sib controls can be increased by increasing either the number of affected sibs per sibship or the number of unaffected control sibs. The sample-size results indicate that the use of sib controls to test for associations, by use of either a single-marker locus or a genomewide screen, will be feasible for markers that have a dominant effect and for common alleles having a recessive effect. The results presented will be useful for investigators planning studies using sibs as controls.     

Socioeconomic factors in the etiology of rheumatic fever

In a case control study we evaluated the effects of socioeconomic and some other factors on the risk of Rheumatic Fever (RF) occurrence. We compared 148 patients, with RF first attack, with 444 controls individually matched to the patients for age, sex, and place of residence. The unemployment of parents was found to be the most closely related to RF, the estimated relative risk (RR) being 10.37 (95 per cent confidence limits 5.31 to 20.24). Among other socioeconomic factors, the following were found to be significantly related to RF: low education of mother, the RR being 2.58 (CL 1.38 to 4.83), change of place of residence during last 5 years, the RR being 5.00 (CL 1.52 to 7.93) and poor living conditions, that is, deteriorated condition of dwellings, the RR being 1.83 (CL 1.12 to 2.98), home dampness, with the RR of 2.48 (CL 1.34 to 4.61) and home crowding expressed as more then 2 persons per room, the RR being 1.72 (CL 1.08 to 2.72), less then 5 m2 of living space per capita, with the RR of 2.83 (CL 1.19 to 6.71) and sleeping in bed with other person, giving the RR of 1.65 (CL 1.02 to 2.66). Out of other factors observed, that were the subject matter of the study, history of frequent sore throat and family history positive on RF were found to be significantly more frequent in patients then in their controls, with corresponding RR of 2.01 (CL 1.41 to 2.89) and 2.81 (CL 1.68 to 4.69) respectively.     

Multifactorial inheritance with cultural transmission and assortative mating. III. Family structure and the analysis of separation experiments.

Demographic data about family composition or structure in the United States is reviewed. About 25% of white children and a majority of black children are reared in either broken or extended families, and this must be taken into consideration for valid studies of cultural inheritance. Atypical family structures are described including those in which parents include: biological parents, stepparents, grandparents, uncles, aunts, sibs, foster parents, and their spouses. General formulae for a wide variety of kinship correlations are derived using path analysis. The multifactorial model presented allows for cultural inheritance, polygenic inheritance, correlated sibling environments, and phenotypic assortative mating (as previously described for intact families) plus extensions necessary for the analysis of separation experiments. These extensions allow for variable family structure and differences in parental influence due to separation, age or stage of development of the child, birth order, or type of relationship. Family structure is observed to have a marked effect on familial resemblance. Computer simulation studies demonstrate marked heterogeneity among phenotypic correlations for kinships of the same degree of genetic relationship arising in different family structures. Analyses of multiple types of sibs and other relatives in variable family structures offer great promise for the study of cultural inheritance.     

Homozygosity by descent for a COL1A2 mutation in two sibs with severe osteogenesis imperfecta and mild clinical expression in the heterozygotes

We report two sibs with severe, progressively deforming osteogenesis imperfecta (OI) and homozygosity by descent for a glycine 751 to serine substitution in the α2(I) collagen chain due to a G to A transition in the COL1A2 gene. The parents, who were first cousins, and two elder sibs were heterozygous for the mutation and presented mild clinical manifestations of OI. Collagen studies on cultured fibroblasts from one of the probands and from the father showed that cells from the homozygote produced only mutant, unstable collagen I, whereas cells from the heterozygote produced both normal and mutant collagen I. This family represents an exceptional example of autosomal recessive OI, caused by homozygosity for a missense mutation in collagen I. Received: 22 July 1996     

A high-frequency polymorphism of NADH-cytochrome b5 reductase in African-Americans

NADH-cytochrome b5 reductase (b5R) is a member of a flavoenzyme family of dehydrogenases-electron transferases that participates in the transfer of electrons from the NADH generated in glycolysis to cytochrome b5. b5R is involved in the steady-state reduction of methemoglobin to hemoglobin in erythrocytes and is also involved in lipid metabolism in other cell types. In a search for mutations of the b5R gene in two unrelated African-American families, a high-frequency polymorphism was detected in the propositi from both families, as well as unrelated normal controls, consisting of a C-to-G transversion in exon 5 that changes threonine to serine at codon 116 (T116S). This is the first polymorphism found in the b5R gene. Using allele-specific PCR on the two propositi, their family members, and unselected populations of African-American, Caucasian, Asian, Indo-Aryan, and Arabic individuals, the C/G polymorphism was found in 26 of 112 African-American chromosomes (allele frequency = 0.23), but not in 108 Caucasian, 46 Asian, 44 Indo-Aryan, or 14 Arabic chromosomes. In preliminary studies, this polymorphism did not correlate with b5R enzyme activity or cause any disease phenotype. It remains to be determined whether this African-specific polymorphism that apparently originated recently in human evolution provides any special survival advantage. Received: 11 April 1996 / Revised: 13 May 1996, 9 August 1996     

Association of MSX1 and TGFB3 with nonsyndromic clefting in humans.

Nonsyndromic cleft lip with or without cleft palate (CL/P) and nonsyndromic cleft palate only (CPO) are common congenital anomalies with significant medical, psychological, social, and economic ramifications. Both CL/P and CPO are examples of complex genetic traits. There exists sufficient evidence to hypothesize that disease loci for CL/P and CPO can be identified by a candidate-gene linkage-disequilibrium (LD) strategy. Candidate genes for clefting, including TGFA, BCL3, DLX2, MSX1, and TGFB3, were screened for LD with either CL/P or CPO in a predominantly Caucasian population, with both case-control- and nuclear-family-based approaches. Previously reported LD for TGFA with both CL/P and CPO could not be confirmed, except in CL/P patients with a positive family history. Also, in contrast to previous studies, no LD was found between BCL3 and either CL/P or CPO. Significant LD was found between CL/P and both MSX1 and TGFB3 and between CPO and MSX1, suggesting that these genes are involved in the pathogenesis of clefting. In addition, a mutation search in the genes DLX2, MSX1, and TGFB3 was performed in 69 CPO patients and in a subset of the CL/P patients. No common mutations were found in the coding regions of these genes; however, several rare variants of MSX1 and TGFB3 were found that may alter the latters' normal function. These results form the basis for future research, including (a) mutation searches in the MSX1 and TGFB3 genes in Caucasian CL/P patients and (b) extension of the search for MSX1 mutations in CPO patients to the noncoding regions.     

Selecting cases from nuclear families for case-control association analysis

We examine the efficiency of a number of schemes to select cases from nuclear families for case-control association analysis using the Genetic Analysis Workshop 14 simulated dataset. We show that with this simulated dataset comparing all affected siblings with unrelated controls is considerably more powerful than all of the other approaches considered. We find that the test statistic is increased by almost 3-fold compared to the next best sampling schemes of selecting all affected sibs only from families with affected parents (AF aff), one affected sib with most evidence of allele-sharing from each family (SF), and all affected sibs from families with evidence for linkage (AF L). We consider accounting for biological relatedness of samples in the association analysis to maintain the correct type I error. We also discuss the relative efficiencies of increasing the ratio of unrelated cases to controls, methods to confirm associations and issues to consider when applying our conclusions to other complex disease datasets.     

Fryns anophthalmia-plus syndrome with hypoplastic adrenal glands

We report a family with two consequent sibs with anophthalmia and cleft lip and palate. A 27 year old woman married to her first cousin was counseled for anophthalmia and cleft lip and palate detected during routine fetal ultrasonographic examination on the 23rd week of the pregnancy. Her obstetric history revealed a healthy girl aged 7 years and a boy with anophthalmia and cleft lip and palate who lived for 20 days in the neonatal intensive care unit. The current pregnancy was terminated after the diagnosis, and post mortem examination of the fetus revealed pre-maxilla agenesis, anophthalmia, cerebral ventricular dilatation, adrenal hypoplasia and single umbilical artery. Chromosome analysis resulted in normal karyotypes of the fetus and both parents. The inheritance pattern was regarded as autosomal recessive and the family was informed about the condition and risks during genetic counseling.     

Relationship of oestrus synchronization method, circulating hormones, luteinizing hormone and prostaglandin F-2 alpha receptors and luteal progesterone concentration to premature luteal regression in superovulated sheep

Ewes were treated with exogenous follicle-stimulating hormone (FSH) and oestrus was synchronized using either a dual prostaglandin F-2 alpha (PGF-2 alpha) injection regimen or pessaries impregnated with medroxy progesterone acetate (MAP). Natural cycling ewes served as controls. After oestrus or AI (Day 0), corpora lutea (CL) were enucleated surgically from the left and right ovaries on Days 3 and 6, respectively. The incidence of premature luteolysis was related (P less than 0.05) to PGF-2 alpha treatment and occurred in 7 of 8 ewes compared with 0 of 4 controls and 1 of 8 MAP-exposed females. Sheep with regressing CL had lower circulating and intraluteal progesterone concentrations and fewer total and small dissociated luteal cells on Day 3 than gonadotrophin-treated counterparts with normal CL. Progesterone concentration in the serum and luteal tissue was higher (P less than 0.05) in gonadotrophin-treated ewes with normal CL than in the controls; but luteinizing hormone (LH) receptors/cell were not different on Days 3 and 6. There were no apparent differences in the temporal patterns of circulating oestradiol-17 beta, FSH and LH. High progesterone in gonadotrophin-treated ewes with normal CL coincided with an increase in total luteal mass and numbers of cells, which were primarily reflected in more small luteal cells than in control ewes. Gonadotrophin-treated ewes with regressing CL on Day 3 tended (P less than 0.10) to have fewer small luteal cells and fewer (P less than 0.05) low-affinity PGF-2 alpha binding sites than sheep with normal CL. By Day 6, luteal integrity and cell viability was absent in ewes with prematurely regressed CL. These data demonstrate that (i) the incidence of premature luteal regression is highly correlated with the use of PGF-2 alpha; (ii) this abnormal luteal tissue is functionally competent for 2-3 days after ovulation, but deteriorates rapidly thereafter and (iii) luteal-dysfunctioning ewes experience a reduction in numbers of small luteal cells without a significant change in luteal mass by Day 3 and, overall, have fewer low-affinity PGF-2 alpha binding sites.     

HLA-DR typing in coeliac disease: evidence for genetic heterogeneity.

Sixty nine propositi from a family study of coeliac disease were typed for HLA-DR antigens. Sixty three (91%) were found to carry the antigen DR3, which was a significantly greater proportion (p = 9.6 X 10(-24] than among the 168 controls (26%). Concurrently 42 children with the disease were DR typed. Not only was the frequency of DR3 significantly increased in these patients (86% versus 26% in controls; p = 3.1 X 10(-12] but so also was the frequency of DR7 (patients 60%, controls 29%; p = 5.8 X 10(-4]. When those propositi whose coeliac disease presented before the age of 20 were combined with the childhood coeliac group and a comparison made between these patients and the remainder of the propositi, all of whom presented when they were older than 20, the childhood onset group had a significant excess of DR7 (p = 2.2 X 10(-3] and a significant deficiency of DR2 (p = 3.5 X 10(-3]. These findings indicate that childhood coeliac disease and adult coeliac disease are genetically heterogeneous.