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We report on two sibs of consanguineous parents with osteogenesis imperfecta, wormian bones, optic atrophy, retinopathy, fits and severe psychomotor retardation.
Two siblings with Larsen syndrome and consanguineous parents are described, both with multiple joint dislocations and the typical facial appearance. Short stature is marked in both children and one had a diaphragmatic hernia which has not been previously described in this condition.
Usher syndrome is a heterogeneous group of disorders of autosomal recessive inheritance characterized by retinitis pigmentosa and congenital sensorineural hearing loss. Two types are accepted clinically: type I is associated with profound congenital deafness with progressive pigmentary retinopathy and total loss of vestibular function. Type II is a milder form, with moderate-to-profound hearing loss and a milder form of retinitis pigmentosa. Vestibular function is preserved. A total of five loci have been identified as accounting for the two distinct phenotypic presentations. We describe a consanguineous family of Pakistani origin whose four children all are affected with Usher syndrome type I. DNA analysis showed non-linkage to any of the loci already identified as tightly linked to the Usher syndrome type I.
We report on three sibs (two females, one male) with a syndrome including physical and mental developmental delay, facial dysmorphia, an increased number of skin folds and recurrent infections. Pulmonary infections were especially severe and frequent, leading to bronchiectasis. Steatorrhea was intermittent. A sweat test was normal. Congenital heart defect was present in two sibs and vesico-ureteral reflux was diagnosed in two sibs. Neutropenia was the most obvious immunological defect. Myelodysplasia was noted. Acute myeloblastic leukemia developed in one sib. The healthy parents of the patients are first cousins. The consanguinity of the parents points-to an autosomal recessive mode of inheritance of this new syndrome but a mitochondrial disorder cannot be excluded.
We report two sibs of consanguineous parents with multiple congenital abnormalities which include prenatal and postnatal growth retardation, anterior segment defects of the eye, arachnodactyly with other skeletal abnormalities, congenital heart disease and early lethality. We think this constellation of anomalies may represent a previously undescribed syndrome. There are some similarities to Michels syndrome from which it should be differentiated.
We report a child of consanguineous parents with microphthalmia and distal limb abnormalities. The association between eye and distal limb abnormalities have been reported previously. However, the eye involvement in the child in this report is less severe than the previously reported cases.
Genealogies of 67 cases of Down syndrome (DS) cytogenetically proven as trisomy 21 born in Saguenay-Lac-Saint-Jean were reconstructed using a population register. Genealogies of three controls for each patient matched on sex, date and place of birth were also reconstructed. The mean kinship coefficient was slightly, but not significantly (p > 0.05), increased in the DS group compared to the control group (0.000222 versus 0.000165). The increase was mostly the result of two patients being related as uncle-nephew. The mean inbreeding coefficient was also higher, although not significantly (p > 0.05), in the DS group than in the control group (0.001348 versus 0.000848). Nine consanguineous marriages (13.4%) were identified in the DS group compared to 17 of 201 (8.5%) in the control group. These results may suggest, as previously reported by Roberts et al. in Shetland, that some recessive element is involved in the etiology of DS, possibly in preventing the loss of the trisomic 21 fetus.
The female proband, from Turkish extraction was the fifth liveborn child of a 24-years-old mother and a 25-years-old father. Her parents as well as her two older sisters and her two older brothers were phenotypically normal. Parents were first cousins. At birth a complex cardiac defect was diagnosed (tricuspid atresia, hypoplasia of the pulmonary artery, dextroposition of the aorta, ventricular septal defect and auricular septal defect) for which she was operated on in 1976, 1983 and 1984. When she was 20 years old, latero aortic pheochromocytoma was diagnosed. At physical examination she had microcephaly (-3DS), mild dysmorphia: long pyramidal nose, short philtrum, short fingers and toes and scoliosis and 6 "café-au-lait" macules suggesting neurofibromatosis, type I. Complex congenital heart defect, microcephaly and pheochromocytoma in a patient with neurofibromatosis type I born from consanguineous parents might be a new association.
To study the genetic determinism of multifactorial diseases in large panmictic populations, a strategy consists in looking for an association with markers closely linked to candidate genes. A distribution of marker genotypes different in patients and controls may indicate that the candidate gene is involved in the disease. In panmictic populations, the power to detect the role of a candidate gene depends on the gametic disequilibrium with the marker locus. In consanguineous populations, we show that it depends on the inbreeding coefficient F as well. Inbreeding increases the power to detect the role of a recessive or quasi-recessive disease-susceptibility factor. The gain in power turns out to be greater for small values of the gametic disequilibrium. Moreover, even in the absence of gametic disequilibrium, the presence of inbreeding may allow to detect the role of a recessive factor. Ignoring inbreeding when it exists may lead to reject falsely a recessive model if the mode of inheritance is inferred on the distribution of genotypes among patients.
Consanguinity analysis can be performed in populations comprising collections of genetic isolates, and the resulting estimates can be valid and useful in phenotypes caused by numerous recessive genes, such as mental retardation and congenital nerve deafness. Maximum likelihood methods are presented for estimating gene frequency and proportions of homozygous cases of morbid phenotypes in such populations.
Consanguinity rates were analyzed in 904 families of retardates studied in 11 Israeli Jewish ethnic groups. It was estimated that the representative recessive gene frequency is .00518, implying that a gene equilibrium maintained by mutation alone is improbable and that some other hypothesis should be considered. The proportions of homozygotes among the following idiopathic subgroups are estimated as follows: 18%-19% homozygotes among severe idiopathic retardates with nonconsanguineous parents and no affected siblings; 74%-76% homozygotes among severe idiopathic retardates with first-cousin parents and no affected siblings; 5% homozygotes among mild idiopathic and idiopathic-familial retardates with nonconsanguineous parents; and 41% homozygotes among mild idiopathic and idiopathic-familial retardates with first-cousin parents. The estimated number of major gene loci within ethnic groups is 17-21 for severe idiopathic retardation and 43-61 for mild idiopathic retardation. These findings provide a basis for genetic counseling of families with single retardates of unknown cause. They can also be useful in epidemiologic studies of nongenetic factors. The great prevalence of common gene defects causing retardation, coupled with the rarity of disorders of amino acid metabolism in the same series, seem to indicate that further emphasis on amino acid metabolism may be nonproductive in the scientific study of retardation and that other biochemical approaches should be encouraged.
Three siblings from a consanguineous marriage were found to have a cleft lip. Two of them developed a progressive retinopathy which was identified as a cone-rod dystrophy. It is suggested that this association may represent a hitherto unreported entity with an autosomal recessive pattern of inheritance, although chance co-occurrence cannot be excluded.
A child of consanguineous parents (first cousins) has spinal muscular atrophy. Two siblings of the mother are similarly effected. In recessive autosomal type of inheritance such close relation of patents increases greatly the risk of having an affected child.
A consecutive sample of 5,000 families of Armed Forces personnel was analysed to study the prevalence of consanguineous marriage and its effect on the prevalence of hereditary gross (physical) malformations. The overall frequency of inbreeding was 76% with a coefficient of 0.04151 which is probably the highest figure reported in literature. The overall prevalence of congenital malformations in children of related parents was 40% (1530 out of 3820) and in non-related parents 26% (305 out of 1180) (p = < 0.01). Considering the prevalence of malformations with the types of relationship of parents, the inter-marriage with first cousins, alone, was highly significant (p = < 0.01).
In a previous nationwide study, we examined the rate of consanguineous matings in the Israeli Arab community. The average inbreeding coefficient was 0.0192, much higher than that reported for the general population of Israel, 0.0038 in 1956-7. The inbreeding coefficients of 69 Arab villages, towns and cities (excluding the Bedouin in the South) were determined. Knowledge of the inbreeding coefficients of the various local populations is of value for geneticists, pediatricians and gynecologists and for planning suitable health programs.
Two patients with identical first and last name, both suffering from Congenital Adrenal Hyperplasia due to 21-hydroxylase deficiency, were investigated in our endocrine outpatient unit. The families of the two girls did not know of each other's existence. Although paternal ancestors were identified up to the 11th and 9th previous generations, respectively, and a common area of origin, roughly 50 km apart, in the northwestern part of the Czech Republic (formerly Austrian Silesia) was established, no common ancestor was found. The patients' respective paternal CYP 21B allele was identical. However, by means of analysis of class I-and class II-HLA regions in both patients and their respective parents no common paternal haplotype was established. In order to still postulate consanguinity by the same paternal haplotype it is necessary to assume that two recombinations in the HLA region must have occurred. The probability that these two events have taken place within the past 11 generations is 0.11%.
Mental abilities and inbreeding. The comparison between 1,302 adults born from consanguineous marriages underlines a heavy depression of mental abilities. The load of inbreeding equals the load of environment, both adding their influences, without interaction. Homozygosity acts probably more particularly on the brain.
In 1988 Greenberg et al. reported an association of fetal hydrops with irregular calcification and moth-eaten skeletal dysplasia. Here, we report on the first case of this disorder accompanied by additional malformations (omphalocele, intestinal malrotation, disturbed fingernails and toes, hypolobated lungs) in a German couple without consanguinity (karyotype 46,XY). Sonograpically, the fetus was characterised by tetraphokomelia, severe generalised hydrops, pulmonal hypoplasia and hepato-splenomegaly. Greenberg dysplasia should be considered in differential diagnosis in cases with severe fetal hydrops and phokomelia on antenatal sonography.