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PubMedDate not supplied

Patterns of inheritance in Irish and Italian families with neural tube defects: comparison between high and low rate areas.

Neural tube defects (NTDs) may result from a genetic susceptibility interacting with environmental exposures occurring early in pregnancy. Current research is concerned with enlarging our understanding of the action of folic acid, a B group vitamin, which has been shown to prevent the occurrence of NTDs in clinical trials. Despite the epidemic waves in the incidence of NTDs and the existence of areas with very high rates, there have been few studies that explored the genetic contribution to NTDs in high rates versus low rate areas. We investigated the genetic epidemiologic factors that occur in NTD families and compared their frequency in a high rate area-Ireland-with a low rate area-Italy. We explored the existence of three features indicative of hereditary factors and found that all three factors were higher in Ireland than in Italy. These factors were (i) sibling recurrence risk (3.3% vs 1.6%; p = 0.2), (ii), other malformations in siblings (11.5% vs 3.3%; p < 0.001) and (iii) average number of children in mothers' families vs fathers' families (average difference in Ireland 1.0 vs 0.4 in Italy; p < 0.1). These results support the motion that geographic differences in occurrence of NTDs are due at least in part to differing prevalences of genetic susceptibility factors. Further epidemiological and molecular studies are needed to confirm this observation. In addition, studies of the interactions between environmental agents and genetic susceptibility will be important in determining their relative contributions.

Child↗

PubMed1998

Mitochondrial A7445G mutation in two pedigrees with palmoplantar keratoderma and deafness.

A New Zealand and a Scottish pedigree with maternally inherited sensorineural deafness were both previously shown to carry a heteroplasmic A7445G mutation in the mitochondrial genome. More detailed clinical examination of the New Zealand family showed that the hearing loss was progressive, with the severity of the overall loss and the frequencies most affected differing markedly between individuals of similar age, and showed that many relatives also had palmoplantar keratoderma. Review of the literature demonstrated three other large families with presumed autosomal dominant inheritance of palmoplantar keratoderma and hearing loss. In a United Kingdom pedigree the syndrome was transmitted by female and male parents, an inheritance pattern which made mitochondrial inheritance unlikely; however, in a Turkish and a Japanese pedigree the affected individuals were all maternally related. Subsequent analysis of the Japanese pedigree documented the same A7445G mitochondrial mutation as was previously found in the New Zealand and Scottish pedigrees. Other mitochondrial sequence variants previously reported in the New Zealand or Scottish pedigrees were absent from the Japanese pedigree which suggests that the A7445G mutation arose independently in all three pedigrees. To our knowledge palmoplantar keratoderma has not previously been associated with mitochondrial defects; however, the current findings suggest that the A7445G mutation is associated not only with progressive hearing loss but also with palmoplantar keratoderma. The penetrance and expressivity of both symptoms varied considerably between individuals in the Scottish and New Zealand Studies which suggests that additional environmental and/or genetic factors are involved.

Adolescent↗

PubMed1998

Genetic analysis of male pattern baldness and the 5alpha-reductase genes.

Genetic predisposition and androgen dependence are important characteristics of the common patterned loss of scalp hair known as male pattern baldness. The involvement of the 5alpha-reductase enzyme in male pattern baldness has been postulated due to its role in the metabolism of testosterone to dihydrotestosterone. There are two known isozymes of 5alpha-reductase. Type I has been predominantly localized to the skin and scalp. Type II, also present on the scalp, is the target of finasteride, a promising treatment for male pattern baldness. We conducted genetic association studies of the 5alpha-reductase enzyme genes (SRD5A1 on chromosome 5 and SRD5A2 on chromosome 2) using dimorphic intragenic restriction fragment length polymorphisms. From a population survey of 828 healthy families comprising 3000 individuals, we identified 58 young bald men (aged 18-30 y) and 114 older nonbald men (aged 50-70 y) for a case control comparison. No significant differences were found between cases and controls in allele, genotype, or haplotype frequencies for restriction fragment length polymorphisms of either gene. These findings suggest that the genes encoding the two 5alpha-reductase isoenzymes are not associated with male pattern baldness. Finally, no clear inheritance pattern of male pattern baldness was observed. The relatively strong concordance for baldness between fathers and sons in this study was not consistent with a simple Mendelian autosomal dominant inheritance. A polygenic etiology should be considered.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗

PubMed1976

Olfacto-genital dysplasia in the female.

The clinical syndrome of OGD in the female is displayed as hypogonadism and most commonly type I hyposmia ("anosmia"). The main pathologic findings are absence of the olfactory bulbs and tracts, hypoplasia of the hypothalamus, a normal pituitary gland, and normal appearing, although unstimulated, ovaries. The syndrome of OGD may be considered as an attenuated form of holoprosencephaly. Various facial abnormalities have been observed in patients with OGD and their families. Thorough neurologic examination may reveal other abnormalities. In the majority of cases the etiology of OGD is not known; however, among about one-fourth of the females, other members of the family exhibit either OGD or anosmia, implying a genetic basis. In this familial form of OGD some pedigrees suggest an X-chromosomal pattern and others, an autosomal inheritance pattern. Although hypogonadotropic hypogonadism is usually considered the only endocrinologic abnormality, stimulatory test of pituitary and hypothalamic function may reveal poor responses of growth hormone. ACTH, prolactin, and possibly MSH. The administration of LRH has shown varying pituitary gonadotropin responses, implying, in some instances, an associated pituitary malfunction. However, these observations may be the result of variations in technic and, therefore, further data are necessary to clarify this issue. Cyclic estrogen and progestin administration stimulates secondary sexual sex characteristics. Exogenous gonadotropins are capable of stimulating ovarian steroidogenesis and, in most patients, inducing ovulation. Thre pregnancies have been reported.

Adolescent↗

PubMed1976

The inheritance of fingerprint patterns.

Analysis of the fingerprints of 571 members of the Habbanite isolate suggest inherited patterns and pattern sequences. A genetic theory has been developed; it assumes that the basic fingerprint pattern sequence is all ulnar loops and that a variety of genes cause deviations from this pattern sequence. Genes that have been proposed include: (1) a semidominant gene for whorls on the thumbs (one homozygote has whorls on both thumbs, the other has ulnar loops on both thumbs and the heterozygote usually has two ulnar loops or one ulnar loop and one whorl); (2) a semidominant gene for whorls on the ring fingers which acts like the gene for whorls on the thumbs; (3) a dominant gene for arches on the thumbs and often on other fingers; (4) one or more dominant genes for arches on the fingers; (5) a dominant gene for whorls on all fingers except for an ulnar loop on the middle finger; (6) a dominant gene for radial loops on the index fingers, frequently associated with an arch on the middle fingers; and (7) a recessive gene for radial loops on the ring and little fingers. These genes may act independently or may show epistasis.

Dermatoglyphics↗

PubMed1991

Parental-specific methylation of an imprinted transgene is established during gametogenesis and progressively changes during embryogenesis.

Genomic imprinting is a regulatory process that requires a cell to recognize the parental origin of alleles. To understand how these alleles are distinguished, we have assessed changes in the DNA methylation of an imprinted transgene as it switches from one inheritance pattern to another while moving through gametogenesis and embryogenesis. We find that both maternally and paternally inherited methylation patterns are erased in primordial germ cells and that distinctive patterns emerge during germ cell maturation. In the case of the maternal allele, the methylation pattern is fully acquired during oogenesis. In the case of the paternal allele, the methylation pattern found in sperm undergoes further modification during embryogenesis. Thus, the distinction between "erased" maternal and paternal alleles is first established during their residence in different germ cells and then may be maintained by the recognition of the distinctive patterns that each allele displays in the zygote.

Alleles↗

PubMed1998

CTG repeats show bimodal amplification in E. coli.

Trinucleotide repeats in human genetic disorders showing anticipation follow two inheritance patterns as a function of length. Inheritance of 35-50 repeats show incremental changes, while tracts greater than 80 repeats show large saltatory expansions. We describe a bacterial system that recapitulates this striking bimodal pattern of CTG amplification. Incremental expansions predominate in CTG tracts < Okazaki fragment size, while saltatory expansions increase in repeat tracts > or = Okazaki fragment size. CTG amplification requires loss of SbcC, a protein that modulates cleavage of single-stranded DNA and degradation of duplex DNA from double-strand breaks. These results suggest that noncanonical single strand-containing secondary structures in Okazaki fragments and/or double-strand breaks in repeat tracts are intermediates in CTG amplification.

Bacterial Proteins↗

PubMed2026

UPDhmm: detecting uniparental disomy from NGS trio data.

SUMMARY: Uniparental disomies (UPDs) are copy-neutral chromosomal alterations that occur when both copies of a chromosome pair (entire or segmental) come from one parent. UPDs, including isodisomies (identical parental chromosome) and heterodisomies (two different homologs from the same parent), reflect meiotic and/or mitotic aberrations of chromosomal segregation that can be associated with congenital or acquired disease. Despite their relevance, current methods to detect UPDs using sequence data (exomes or genomes) have limited sensitivity for small events, cannot precisely determine the UPD sub-type or coordinates, and perform poorly when including individuals or populations with consanguinity. We present UPDhmm, a novel tool that uses trio-based sequence data (proband and parents) and models inheritance patterns. UPDhmm predicts the most likely inheritance scenario, normal Mendelian inheritance versus UPD event, based on genotype combinations using a Hidden Markov Model (HMM). We validated the method using simulations on exome and genome data from 1000-Genomes projects. UPDhmm overperformed currently available methods in detecting simulated UPD events in both data types. We applied UPDhmm to a collection of nearly 2400 families with a proband with autism spectrum disorder (Simons Simplex Collection Project) and identified UPD events in two affected individuals, one of them previously unreported. These two events, a paternal isodisomy of chr8 and a maternal heterodisomy of chr22, can be genetic causes of the disease, demonstrating the clinical utility of UPDhmm. Thus, UPDhmm can facilitate the incorporation of UPD detection into clinical pipelines of genomic analysis. AVAILABILITY AND IMPLEMENTATION: UPDhmm is implemented in R and is available in the Bioconductor package (version 1.5.0): https://www.bioconductor.org/packages/release/bioc/html/UPDhmm.html. The source code can be found at https://github.com/martasevilla/UPDhmm under the MIT license.

Uniparental Disomy↗

PubMed2026

A Novel SLC25A4 Variant Causing Mitochondrial Dysfunction, Myopathy and Cardiomyopathy: A Functional and Molecular Characterization.

SLC25A4, solute carrier family 25 member 4, gene is a member of the mitochondrial carrier subfamily within the solute carrier protein family. Pathogenic variants in SLC25A4 are associated with a spectrum of mitochondrial disorders that exhibit variable inheritance patterns and clinical manifestations. Specifically, dominantly inherited variants are typically associated with progressive external ophthalmoplegia with mitochondrial DNA deletions, recessively inherited variants are linked to myopathy and cardiomyopathy, and de novo variants can result in early-onset fatal disease presentations. In this study, we aimed to identify and characterize the disease-causing mutation(s) in a nine-year-old female patient from a consanguineous Saudi family. The patient was asymptomatic until the age of 3 years, when she presented with cardiomyopathy and myopathy. Comprehensive genetic analysis inclusive of whole exome sequencing and segregation analysis using Sanger sequencing identified an SLC25A4 variant (NM_001151.4: exon 2: c.112-1G>C) as the most likely cause of the disease. To assess transcript-level effects, we performed RT-PCR on RNA extracted from the patient's cultured lymphoblast cell lines (LCLs) and fibroblast cell lines (FCLs). RT-PCR analysis demonstrated that the variant causes aberrant splicing, resulting in a 6 bp in-frame deletion (p.Gln37_Val38del) in the ANT1 protein. Quantitative RT-PCR demonstrated reduced SLC25A4 transcript levels in both FCLs and LCLs. Quantitative PCR analysis of mitochondrial DNA demonstrated a trend toward increased mtDNA copy number in patient-derived FCLs compared with controls, suggesting a possible compensatory response to mitochondrial dysfunction. Furthermore, Seahorse assays revealed marked reductions in both oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) in patient-derived FCLs compared with controls. These findings expand the molecular and functional spectrum of SLC25A4-associated disease and may inform clinical practice, including genetic interventions such as preimplantation genetic diagnosis, premarital genetic screening, targeted genetic counseling, and cascade testing of at-risk family members.

Humans↗

PubMed1991

Molecular genetic approaches to the study of individual risk in alcoholism.

Genetic studies of alcoholics, their families and controls have given credence to the idea that genetic influences in alcoholism exist, and set the stage for efforts to identify alcoholism-susceptibility genes (Devor and Cloninger, 1989). My purpose is not to review the genetics of alcoholism, but rather to review the genetic approaches that have been successful in identifying the genes responsible for genetic conditions such as muscular dystrophy and cystic fibrosis. In these disorders our current knowledge of the basic biochemical defect was derived directly from the cloning of the gene that is defective in the disorder. The cloned gene provides DNA probes for carrier identification and prenatal diagnosis, while knowledge of the basic defect allows new and direct investigation of potential therapeutic strategies. The genetic approach is much less definitive when it comes to the study of polygenic or multifactorial disorders such as schizophrenia or Alzheimer's disease. In the case of alcoholism the problem is exacerbated not only by environmental factors but also by phenotypic and genetic heterogeneity. The lack of a clear inheritance pattern means that plausible modes of inheritance must be invoked and tested on families with multiple affected members. Direct segregation analysis may not be possible and the less informative analysis of sib-pairs may be the method of choice. Ultimately, however, it should be possible to identify and clone those genes that play a major role in determining susceptibility to alcoholism. Once cloned, the protein products can be identified, and study of their function should lead to new understanding of the complex biological processes involved in this disorder.

Alcoholism↗

PubMed1995

Patterns of maternal transmission in bipolar affective disorder.

The mode of inheritance of bipolar affective disorder (BPAD) appears complex, and non-Mendelian models of inheritance have been postulated. Two non-Mendelian phenomena, genomic imprinting and mitochondrial inheritance, may contribute to the complex inheritance pattern seen in BPAD. Both imprinting and mitochondrial inheritance share the feature of differential expression of the phenotype, depending on the parent of origin. In this study we tested the hypothesis of a parent-of-origin effect on the transmission of BPAD. We examined the frequency and risk of affective disorder among relatives in a sample of 31 families ascertained through treated probands with BPAD and selected for the presence of affected phenotypes in only one parental lineage. Three specific comparisons were performed: (1) the observed frequency of transmitting mothers versus transmitting fathers; (2) the observed frequency and lifetime risk of BPAD among the maternal versus the paternal relatives of probands; and (3) the observed frequency and lifetime risk of BPAD for the offspring of affected mothers compared with the offspring of affected fathers. We observed a higher than expected frequency of affected mothers (P < .04), a 2.3-2.8-fold increased risk of illness for maternal relatives (P < .006), and a 1.3- 2.5-fold increased risk of illness for the offspring of affected mothers (P < .017). In seven enlarged pedigrees, fathers repeatedly failed to transmit the affected phenotype to daughters or sons. Taken together, these findings indicate a maternal effect in the transmission of BPAD susceptibility and suggest that molecular studies of mtDNA and imprinted DNA are warranted in patients with BPAD.

Bipolar Disorder↗

PubMed1998

Risk factors for endometrial cancer according to familial susceptibility.

Endometrial cancer (EC) shares some environmental or genetic risk factors with colorectal cancer (CRC). It represents a risk factor for CRC. Furthermore, EC is the most frequent extracolonic neoplasm in HNPCC (hereditary nonpolyposis colorectal cancer) and, in this syndrome, it has the same inheritance pattern as CRC. Neoplastic family history and clinical features were evaluated in women with EC in a health care district (Pordenone Province) in Northeastern Italy from 1990 to 1995, to examine the proportion of patients with hereditary cancer and the relation with clinical characteristics of EC. We interviewed 215 patients with EC (average age 61 years, range 35-88) in relation with some risk factors (age, weight, diabetes, menstrual and reproductive pattern, synchronous and metachronous neoplasms) and we obtained their family pedigree. Twenty-nine patients (13.5%) had a CRC family history, 66 (30.7%) showed an aspecific cancer aggregation in their families and more than half (120, 55.8%) had a negative cancer family history. Family pedigrees were consistent with a dominant inherited cancer pattern in 8 patients (3.7%) belonging to the CRC-related family history group. A different pattern of family history distribution emerged in relation with age (< 55 vs. > or = 55, p < 0.001) and body mass index (BMI) (< 26 vs. > or = 26, p = 0.002). Patients with a CRC pedigree were more numerous in the younger group, in the group with lower BMI and in pre-menopausal women.

Adolescent↗

PubMed1985

Maternally inherited mitochondrial myopathy and myoclonic epilepsy.

A family is described with familial myoclonic epilepsy associated with mitochondrial myopathy. The disorder follows a maternal inheritance pattern consistent with a mitochondrial DNA (mtDNA) mutation. The large kindred permitted exclusion of autosomal dominant, recessive, and X-linked patterns of transmission. Several characteristics of the inheritance and variability of expression within the pedigree are consistent with recently acquired knowledge about the genetics of human mtDNA. The clinical spectrum of disease is compatible with a proportionality model of mutant and wild-type mtDNAs. Muscle biopsies of affected patients showed an increased number of abnormal muscle mitochondria. Serum levels of pyruvate or pyruvate and lactate were elevated. The most severely affected patient had constant myoclonic jerking, dementia, ataxia, spasticity, hearing loss, and hypoventilation. Cerebral dysfunction in patients with mild involvement was marked by prominent photic driving seen on electroencephalograms and high-amplitude visual and somatosensory evoked responses but no myoclonus, ataxia, or dementia. The individual clinical features of the disease worsen over time for all patients; however, mildly affected patients have not become moderately affected and moderately affected patients have not become severely affected.

Adult↗

PubMed1995

Correlations between familial refractive error and children's non-cycloplegic refractions.

We examined the spherical equivalent refractions of 237 subjects who had been seen four or more times in a longitudinal study of refractive development in normal children. We employed both photorefraction and autorefraction using a Canon R1 autorefractor. We performed an analysis of variance (F-test for Lack of Fit) to determine the significance of a linear regression in fitting these refractions against three different measures of familial refractive status. One measure included only the number of myopic parents, a second took into account the number of hyperopic parents, and a third included the refractive states of extended genetic relatives. We found no significant correlation between photorefractive data and familial refractions; however, we did find significant, albeit weak, correlations between all measures of familial refractive status and infrared autorefractions of their children. A linear relationship between autorefractive data and overall familial refractive state was found to be most significant. Linear regression of children's autorefractions against a measure of parental myopia and hyperopia was less significant, while a linear model fitting only a measure of parental myopia was least significant, in addition to showing other non-linear trends. We attribute the failure to find a significant correlation between parent and offspring refractions using children's photorefractive data to vignetting by the apparatus and to the short distance of the fixation target. We believe the significant correlation patterns found with the autorefractor reflect the inheritance patterns of parental and familial refractive states.

Adolescent↗

PubMed2002

Clinical and ultrastructural features of a novel hereditary anterior segment dysgenesis.

OBJECTIVE: To describe the clinical, histopathologic, and hereditary features of a novel familial anterior segment dysgenesis. DESIGN: Prospective, observational case series and interventional case report. PARTICIPANTS: Ten individuals from three generations of a single family with iris and corneal abnormalities associated with congenital cataracts. MAIN OUTCOME MEASURES: An ophthalmic evaluation including slit-lamp examination, corneal topography, pachymetry, and specular biomicroscopy of all family members, and histopathologic and ultrastructural evaluation of one excised corneal button. RESULTS: The proband was an 81-year-old man with bilateral aphakia and diffuse corneal haze, and thinning associated with corneal guttae. His pupils were small, mildly eccentric, and difficult to dilate. Pachymeter readings were 335 microm (right eye) and 330 microm (left eye). Topography confirmed advanced steepening of both corneas. Light microscopic and transmission electron microscopic examinations of the corneal button revealed an attenuated endothelium with prominent intracellular random aggregates of small-diameter filaments staining positively for cytokeratin. Descemet's membrane was thickened and had marked posterior nodularity. Various-sized polymorphic vacuoles containing layered electron-dense material were present within and between collagen lamellae and within keratocytes throughout the stroma and Bowman's membrane. Secondary bullous changes of the epithelium with thickening of the basement membrane were also observed. The family pedigree demonstrated an autosomal dominant inheritance pattern. CONCLUSIONS: This constellation of autosomal dominantly inherited corneal endothelial and stromal disorder, with congenital cataracts and iris abnormalities, represents a novel anterior segment disorder. Its etiology may involve an abnormal migration of the secondary mesenchyme.

Adolescent↗

PubMed2002

Differential CO(2)-induced c-fos gene expression in the nucleus tractus solitarii of inbred mouse strains.

Genetic determinants confer variation between inbred mouse strains with respect to the magnitude and pattern of ventilation during hypercapnic challenge. Specifically, inheritance patterns derived from low-responsive C3H/HeJ (C3) and high-responsive C57BL/6J (B6) mouse strains suggest that differential hypercapnic ventilatory sensitivity (HCVS) is controlled by two independent genes. The present study also tests whether differential neuronal activity in respiratory control regions of the brain is positively associated with strain variation in HCVS. With the use of whole body plethysmography, ventilation was assessed in C3 and B6 strains at baseline and during 30 min of hypercapnia (inspired CO(2) fraction = 0.15, inspired O(2) fraction = 0.21 in N(2)). Subsequently, in situ hybridization histochemistry was performed to determine changes in c-fos gene expression in the commissural subnucleus of the nucleus tractus solitarius (NTS). During hypercapnia, breathing frequency and tidal volume were significantly (P < 0.01) different between strains: C3 mice showed a slow, deep-breathing pattern relative to a rapid, shallow phenotype of B6 mice. CO(2)-induced increase in c-fos gene expression was significantly (P < 0.01) greater in NTS regions of B6 compared with C3 mice. In this genetic model of differential HCVS, the results suggest that a genomic basis for varied hypercapnic chemoreception or transduction confers greater afferent neuronal activity in the caudal NTS for high-responsive B6 mice compared with low-responsive C3 mice.

Animals↗

PubMed1987

Dental development and the pharyngeal lymphoid tissue.

Because the teeth are housed and develop within the jaws, skeletal development of the maxilla and mandible is a primary factor in the consideration of any problems pertaining to the developing dentition. Growth of the posterior nasal choanae, the maxilla, and the nasopharynx should be evaluated as a unit in assessing the favorable or unfavorable character of the nasopharyngeal region. Both large and small adenoidal tissues should be examined in light of the morphologic character of the nasopharynx (be it small, large, narrow, or wide) and related to the developing maxilla. Variables in size and location of the maxilla and the pharynx will play an important role in the impact that lymphoid tissue will have on the patency of the nasopharyngeal isthmus. Synchronized growth between the normally developing adenoids and the migration of the maxilla away from the cranial base will produce a balanced environment that precludes nasal obstruction by the presence of adenoids. With time, the changes in spatial relationships between the posterior border of the maxilla and the posterior pharyngeal wall plus atrophy of the adenoidal tissue will generally minimize or eliminate the problems of nasal obstruction and mouth breathing. Growth data may be used to evaluate the status, assess progress, measure comparability, determine inheritance patterns, and confer individuality. Unit-trait inheritance of the teeth, alveolar processes, maxilla, mandible, soft-tissue profile, tongue, pharynx, and lymphoid tissues may well produce more definitive answers to the question of the developing dentition and the pharyngeal lymphoid tissue. Finally, at present, no clinician can categorically state that enlarged tonsils or adenoids per se are responsible for abnormal dentition in the absence of other factors.

Adenoids↗

PubMed1996

[A familial case of keratoconus with corneal granular dystrophy].

We report a familial case of keratoconus with corneal granular dystrophy. The mother and first son have both keratoconus and corneal granular dystrophy and the second son has keratoconus alone. The keratoconus in this family is thought to be an autosomal dominant or an X-linked inheritance pattern. Granular dystrophy is an autosomal dominant inheritance. This familial case suggests that the gene loci of the two diseases are close together or have a close relationship.

Adolescent↗