Rate of chromosomal aberrations in prenatally detected hydrops fetalis and hygroma colli

Summary Chromosome analyses were carried out in a series of 775 fetuses with morphological abnormalities diagnosed by ultrasound. Among these cases, 57 demonstrated non-immune hydrops fetalis with hygroma colli (group 1) and a further 116 non-immune hydrops fetalis without hygroma colli (group 2). Different chromosome abnormalities were found in 54.5% of cases of group 1 where chromosome analyses could be performed, and in 27.6% of cases of group 2. The most common aberrations were monosomy X and trisomy 21.     

Non-immune fetal hydrops associated with nuchal cystic hygroma: further evidence for an autosomal recessive subtype.

Nuchal cystic hygroma (NCH) and non immune hydrops (NIH) were detected by ultrasound examinations in two sib male fetuses. Fetal and parental karyotypes were normal. The parents elected to terminate the two pregnancies. Post mortem examination showed no anomalies other than those detected by ultrasound. The family history shows consanguinity supporting the hypothesis, in this family, of an autosomal recessive inheritance of the cystic hygroma/non immune hydrops.     

Morphological study of the removed fetus after therapeutic abortion for echographic anomalies (apropos of 42 cases)

In 42 cases, fetal abnormalities were diagnosed by obstetric ultrasonography and the pregnancy was terminated. The malformations included: anencephaly (22), severe hydrocephaly (4, one with a spina bifida), encephalocele and meningocele (2) amniotic band syndrome (4; a correct prenatal diagnosis was performed during the second trimester in two cases), major anterior abdominal wall defects (2), Pena-Shokeir syndrome type I? (I), severe renal abnormalities (2), conjoined twins, dicephalus type (2), cystic hygroma and hydrops fetalis (2), osteogenesis imperfecta, type II (I). Thus, there were 23 fetuses with a polygenetically determined status; five fetuses could be affected by an autosomal recessive disorder.     

Hypertrichosis cubiti: two new cases and a review of the literature

Two cases of hypertrichosis cubiti in combination with short stature, facial dysmorphias and retarded development are reported with a review of the literature. Hypertrichosis cubiti, the hairy elbows syndrome, consists of a localized form of long vellus hair on the extensor surfaces of the distal third of the upper arm and the proximal third of the forearm bilaterally. It can be associated with short stature and other physical abnormalities. The mode of inheritance has not been established yet; an autosomal recessive as well as an autosomal dominant inheritance trait are postulated.     

Genetically determined asynapsis, spermatogenic degeneration, and infertility in men.

We report a family in which azoospermia and infertility affected two sibs whose parents were first cousins once removed. Meiotic cells of the proband, who had the chromosomal complement of a normal male (46,XY), exhibited asynapsis, defective synaptonemal complex (SC) formation, chiasma failure, and degeneration of prophase spermatocytes with asynapsis. Based on these observations, we suggest that the meiotic abnormalities and infertility in this family comprise a trait with an autosomal recessive mode of inheritance. Review of published cases of infertile men with normal chromosomal complements and disturbed meiosis suggests that genetically determined asynapsis and desynapsis similar to that established in plant and insect species also occur in humans. In humans, asynapsis appears to be inherited as an autosomal recessive. The mode of inheritance of desynapsis is not clear; X-linked recessive or autosomal dominant has been suggested in one family. Studies by us and by others reported in the literature suggest that the mode of action of genes that affect synapsis and cause a reduction in the numbers of visible chiasmata at diakinesis is dissimilar to that of the action of genes that cause defective meiotic recombination, defective repair of induced damage to DNA in somatic cells, and chromosome instability.     

Segregation analyses of the index fingerprint

Segregation analyses have been performed on both the ridge count and the pattern type (arch vs. nonarch) of the index fingerprints in a sample of 422 families. These analyses suggest a dominant autosomal major gene for arch and a recessive autosomal gene for low ridge count on the index finger. In both cases, multifactorial inheritance has to be taken into account. However, by testing different hypotheses, it turns out that the penetrance of arch trait is low (70%), and that the transmission parameters of the ridge count trait, although they are significant, diverge from the expected Mendelian values.     

Kyphomelic dysplasia: a report of a family with an autosomal dominant pattern.

Kyphomelic dysplasia (KD) is a rare autosomal recessive entity characterized by shortening and bowing of the limbs, skin dimples, abnormalities of methaphysis and ribs, a short trunk, a narrow thorax, neonatal respiratory distress, platyspondyly, and facial dysceptism with micrognathia, midfacial hypoplasia, and a broad nasal bridge. Some children die in early infancy. The survivors show normal hands, feet, cranium and psychomotor development. The condition varies in severity. The facial features and bowing improve during childhood, and stature remains short during adulthood. We report here a family with KD inherited as an autosomal dominant trait, which appears to be less severe than the autosomal recessive form, without facial and vertebral a favorable outcome and with involvement and final short stature.     

Idiopathic hemochromatosis: demonstration of homozygous-heterozygous mating by HLA typing of families

Summary In five families with idiopathic (hereditary) hemochromatosis, clinical and biochemical expression of the disease occurred in offspring of probands, suggesting an autosomal dominant mode of inheritance. However, HLA typing of subjects indicated that a homozygous-heterozygous mating almost certainly had occurred in four of the five families, resulting in homozygous offspring. Thus, in these families inheritance of the hemochromatosis trait was best explained in terms of an autosomal recessive or intermediate mode of inheritance. This study demonstrates the value of HLA typing in identifying homozygous-heterozygous matings in hemochromatosis families.     

Detection of New Paternal Dystrophin Gene Mutations in Isolated Cases of Dystrophinopathy in Females

Duchenne muscular dystrophy is one of the most common lethal monogenic disorders and is caused by dystrophin deficiency. The disease is transmitted as an X-linked recessive trait; however, recent biochemical and clinical studies have shown that many girls and women with a primary myopathy have an underlying dystrophinopathy, despite a negative family history for Duchenne dystrophy. These isolated female dystrophinopathy patients carried ambiguous diagnoses with presumed autosomal recessive inheritance (limbgirdle muscular dystrophy) prior to biochemical detection of dystrophin abnormalities in their muscle biopsy. It has been assumed that these female dystrophinopathy patients are heterozygous carriers who show preferential inactivation of the X chromosome harboring the normal dystrophin gene, although this has been shown for only a few X:autosome translocations and for two cases of discordant monozygotic twin female carriers. Here we study X-inactivation patterns of 13 female dystrophinopathy patients—10 isolated cases and 3 cases with a positive family history for Duchenne dystrophy in males. We show that all cases have skewed X-inactivation patterns in peripheral blood DNA. Of the nine isolated cases informative in our assay, eight showed inheritance of the dystrophin gene mutation from the paternal germ line. Only a single case showed maternal inheritance. The 10-fold higher incidence of paternal transmission of dystrophin gene mutations in these cases is at 30-fold variance with Bayesian predictions and gene mutation rates. Thus, our results suggest some mechanistic interaction between new dystrophin gene mutations, paternal inheritance, and skewed X inactivation. Our results provide both empirical risk data and a molecular diagnostic test method, which permit genetic counseling and prenatal diagnosis of this new category of patients.     

Structure of the gene for congenital nephrotic syndrome of the finnish type (NPHS1) and characterization of mutations.

Congenital nephrotic syndrome of the Finnish type (NPHS1) is an autosomal recessive disorder that is caused by mutations in the recently discovered nephrin gene, NPHS1 ({"type":"entrez-nucleotide","attrs":{"text":"AF035835","term_id":"3025698","term_text":"AF035835"}}AF035835). The disease, which belongs to the Finnish disease heritage, exists predominantly in Finland, but many cases have been observed elsewhere in Europe and North America. The nephrin gene consists of 29 exons spanning 26 kb in the chromosomal region 19q13.1. In the present study, the genomic structure of the nephrin gene was analyzed, and 35 NPHS1 patients were screened for the presence of mutations in the gene. A total of 32 novel mutations, including deletions; insertions; nonsense, missense, and splicing mutations; and two common polymorphisms were found. Only two Swedish and four Finnish patients had the typical Finnish mutations: a 2-bp deletion in exon 2 (Finmajor) or a nonsense mutation in exon 26 (Finminor). In seven cases, no mutations were found in the coding region of the NPHS1 gene or in the immediate 5''-flanking region. These patients may have mutations elsewhere in the promoter, in intron areas, or in a gene encoding another protein that interacts with nephrin.     

Family studies of mephenytoin hydroxylation deficiency.

A genetic polymorphism characterized by deficient drug oxidation exists for the hydroxylation of mephenytoin. This deficiency was first recognized in a family study that suggested an autosomal recessive pattern of inheritance. To confirm the observation, we investigated 28 relatives of five poor metabolizers. Subjects ingested 50 mg of mephenytoin, and the 24-hr urine was analyzed for hydroxymephenytoin. The pedigree data shown here provide strong evidence that deficient mephenytoin hydroxylation is an autosomal recessive trait.     

Autosomal Recessive Transmission of MYBPC3 Mutation Results in Malignant Phenotype of Hypertrophic Cardiomyopathy

Background

Hypertrophic cardiomyopathy (HCM) due to mutations in genes encoding sarcomere proteins is most commonly inherited as an autosomal dominant trait. Since nearly 50% of HCM cases occur in the absence of a family history, a recessive inheritance pattern may be involved.

Methods

A pedigree was identified with suspected autosomal recessive transmission of HCM. Twenty-six HCM-related genes were comprehensively screened for mutations in the proband with targeted second generation sequencing, and the identified mutation was confirmed with bi-directional Sanger sequencing in all family members and 376 healthy controls.

Results

A novel missense mutation (c.1469G>T, p.Gly490Val) in exon 17 of MYBPC3 was identified. Two siblings with HCM were homozygous for this mutation, whereas other family members were either heterozygous or wild type. Clinical evaluation showed that both homozygotes manifested a typical HCM presentation, but none of others, including 5 adult heterozygous mutation carriers up to 71 years of age, had any clinical evidence of HCM.

Conclusions

Our data identified a MYBPC3 mutation in HCM, which appeared autosomal recessively inherited in this family. The absence of a family history of clinical HCM may be due to not only a de novo mutation, but also recessive mutations that failed to produce a clinical phenotype in heterozygous family members. Therefore, consideration of recessive mutations leading to HCM is essential for risk stratification and genetic counseling.     

Thrombophilia gene mutations in oculoauriculovertebral spectrum

Oculoauriculovertebral spectrum or Goldenhar syndrome is a phenotypically and probably genetically heterogeneous disorder characterized by hemifacial microsomia (unilateral ear abnormalities and ipsilateral mandibular hypoplasia) as well as vertebral anomalies and epibulbar dermoid/lipodermoids. Although most cases of the Goldenhar syndrome are sporadic, both autosomal recessive and dominant inheritance have been reported so far. In this report, we describe the clinical aspects of two familial cases with evidence of autosomal dominant inheritance and a non-familial case, and compare them with the reports in the literature. One of our familial cases was a ten day old female infant of a mother with left hemifacial microsomia. She had multiple bilateral preauricular tags and a "fleshy masse" on her right cheek. The other familial case was a two months old male infant whose father had hemifacial asymmetry. He had unilateral microtia, and abnormal antihelix, a skin tag in the contralateral ear associated with bilateral sensorineural hearing loss. The third case was a sporadic case who was 2 years old boy with preauricular skin tag, right hemifacial microsomia and limbal dermoid at the temporal limbus of the right eye. As there were no other associated defects, the cases we presented here were thought to be mild variations of the Goldenhar spectrum. The most commonly encountered mutations of thrombophilia genes were studied. We believe that the interfamilial and intrafamilial clinical variabilities observed in these cases reinforce the necessity of a careful examination for the whole family with regards to the stigmata of Goldenhar syndrome.     

Genetic hemochromatosis and HLA linkage

Summary We previously reported five families with primary, genetic (idiopathic) hemochromatosis in whom HLA typing of subjects indicated that a homozygous-heterozygous mating had almost certainly occurred and in whom inheritance of the disease trait was best explained by an autosomal recessive mode of inheritance. However, in one family, two children apparently homozygous for hemochromatosis did not manifest overt evidence of the disease, and alternative explanations were postulated, including autosomal dominant inheritance in this family. Subsequent study of the family members, including repeat HLA-DR serology with more recently defined antisera and DNA genotyping at the HLA-DR locus has, we believe, provided the true explanation for the previous apparent anomaly and adds further evidence for the tight linkage of the disease to the HLA-A locus.     

Co-recessive inheritance: a model for DNA repair and other surveillance genes in higher eukaryotes.

The co-recessive inheritance hypothesis proposes that certain recessively inherited diseases require homozygosity and/or hemizygosity for defective alleles at more than one locus simultaneously for the trait to be expressed. Although this hypothesis was originally proposed in the context of defective alleles for genes coding for DNA-repair functions, it need not be limited to this context, and genetic selection pressure may favor this model for genes involved in surveillance of any type. The co-recessive inheritance hypothesis also predicts extremely high carrier frequencies, likely affecting much of the general population, for defective alleles associated with these rare recessive diseases. The model predicts much lower rates of consanguinity between the parents of affected individuals than autosomal recessive inheritance, allowing it to be tested epidemiologically, and recent data suggest that the hypothesis may be valid for some cases of ataxia telangiectasia and xeroderma pigmentosum. The model provides possible explanations for a number of otherwise puzzling findings in several diseases associated with defective DNA repair.     

The use of exclusive trios in human pedigrees to determine autosomal or X-linked dominance or recessiveness

Four rules of judgement, each involving one child and its parents, can rule out one common mode of inheritance each, namely dominance, or recessiveness, autosomal or sex-linkage. A large pedigree usually provides three different groups of ? particular child and its parents. Each such trio may rule out one particular mode of inhe itance. When both parents show a trait but one daughter does not, the trait cannot be recessive. When no parent shows the trait but one son or daughter does, the trait cannot be dominant. Again, if a father shows a trait but his daughter and her mother do not show it, the trait cannot be sex-linked dominant. And when a mother shows a trait, but her son and his father do not, the trait cannot be sex-linked recessive. A pedigree having three of these four different sets of “parents-and-child” groups, rules out three modes of inheritance for the trait in question, and thereby confirms that the mode of inheritance for the trait is, as a rule, the single remaining mode of the four.     

XY gonadal dysgenesis: Genetic heterogeneity based upon clinical observations,H-Y antigen status and segregation analysis

Summary Clinical observations and segregation analysis indicate that XY gonadal dysgenesis is characterized by genetic heterogeneity. In addition to the type inherited in X-linked recessive fashion, segregation analysis of other families suggested another type by revealing that the proportion of affected sibs did not differ from that expected on the basis of a male-limited autosomal recessive inheritance. Further heterogeneity may be deduced on the basis of coexisting campomelic dwarfism or possibly also renal parenchymal abnormalities. These observations of genetic heterogeneity must be considered when interpreting studies in which individuals with XY gonadal dysgenesis may or may not show H-Y antigen.     

Hereditary hemolytic anemia with erythrocyte pyrimidine 5′-nucleotidase deficiency in Spain

Summary We report a hereditary hemolytic anemia associated with a severe erythrocyte pyrimidine 5-nucleotidase deficiency in a Spanish family of five members in which the parents are first cousins. Both parents exhibited decreased nucleotidase activity without clinical or hematologic abnormalities. Two children (a male and a female) showed severe pyrimidine 5-nucleotidase deficiency with hemolytic anemia. The remaining child (a male) showed no signs of the disease. The findings strongly suggest an autosomal recessive mode of inheritance in this enzymopathy. This seems to be the first report of pyrimidine 5 nucleotidase deficiency in Spain.     

家族高发性2型糖尿病的遗传模式研究

对1999～2000年门诊及住院的家族高发性2型糖尿病患者为先证者的136个大家系进行研究,以探讨该病的遗传模式。对家系人群采用Falconer 法估算遗传率,用Penrose法进行多基因分析,并用S.A.G.E-REGD软件拟合A型回归Logistic模型进行复合分离分析的方法,对家族高发性2型糖尿病家系进行研究。结果表明,136个大家系的2型糖尿病遗传率为94.07%±5.84%,提示在这些家系中可能有显性主基因存在。多基因分析研究表明,在该人群中,2型糖尿病因性别不同而存在两种遗传模式。复合分离分析拒绝单纯环境模型、非传递模型、共显性模型,接受隐性模型和显性模型,但隐性模型为最佳遗传模式。因此,2型糖尿病具有高度的遗传性和遗传异质性,总体表现为多因子遗传,在部分遗传背景较一致的家系人群中可能存在由主要基因决定的常染色体显性遗传。 Abstract:This study is to explore the genetic model of type 2 diabetes mellitus (type 2 DM) among the hereditary family.One hundred and thirty-six pedigrees of familial type 2 DM were studied.The heritability of type 2 DM was estimated according to Falconer's method and the multi-factorial inheritance analyzed according to Penrose's method.Complex segregation analysis was performed using S.A.G.E-REGD.The heritability of familial type 2 DM was 9407%±5.84%.Dominant major gene might influence the genesis of type 2 DM.Analysis of multi-factorial inheritance indicated that there be two genetic patterns respectively in male and female populations.By complex segregation analysis,environment,non-transmitted and co-dominant inheritance were rejected.Autosomal dominant (AD) inheritance and autosomal recessive (AR) inheritance was accepted but AR inheritance was the best pattern.This study suggested that type 2 DM had significant heritability and genetic heterogeneity,which appeared to be a disease of multi-factorial inheritance generally and autosomal dominant (AD) inheritance in part of pedigrees.     

Genome scans provide evidence for low-HDL-C loci on chromosomes 8q23, 16q24.1-24.2, and 20q13.11 in Finnish families

We performed a genomewide scan for genes that predispose to low serum HDL cholesterol (HDL-C) in 25 well-defined Finnish families that were ascertained for familial low HDL-C and premature coronary heart disease. The potential loci for low HDL-C that were identified initially were tested in an independent sample group of 29 Finnish families that were ascertained for familial combined hyperlipidemia (FCHL), expressing low HDL-C as one component trait. The data from the previous genome scan were also reanalyzed for this trait. We found evidence for linkage between the low-HDL-C trait and three loci, in a pooled data analysis of families with low HDL-C and FCHL. The strongest statistical evidence was obtained at a locus on chromosome 8q23, with a two-point LOD score of 4.7 under a recessive mode of inheritance and a multipoint LOD score of 3.3. Evidence for linkage also emerged for loci on chromosomes 16q24.1-24.2 and 20q13.11, the latter representing a recently characterized region for type 2 diabetes. Besides these three loci, loci on chromosomes 2p and 3p showed linkage in the families with low HDL-C and a locus on 2ptel in the families with FCHL.