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PubMed2005

Endogamy, consanguinity and community disease profiles.

Considerable attention is paid to the role of consanguineous marriage as a causative factor in the prevalence of genetic disorders. At the same time, the potential influence of community endogamy on overall levels of homozygosity and disease profiles remains largely under-investigated. With the ongoing global epidemiological transition from infectious to non-communicable disease, the impact of genetic disorders will become increasingly important and a thorough understanding of the determinants of human population-genetic structure will be all the more necessary. In particular, the genetic components of adult-onset diseases will become more obvious and assume greater significance. Similarly, refinements of study design to incorporate intercommunity genetic variation appear to be an essential prerequisite in pharmacogenetic research if the concept of individualized treatments is to achieve reality, with equivalent subject-control comparison difficulties also predicted in forensic genetics.

Consanguinity↗

PubMed1975

Consanguinity and demography in some Chilean populations.

Spatial and temporal changes in the rates and the patterns of consanguinity are studied in some (indigenous as well as admixed) populations of Chile. Relationship between the variation of infant mortality and late fetal death rates with the degree of inbreeding is also explored. The need of a temporal study of these demographic variables is also emphasized to elucidate the influence of marriage structure or determined reproductive patterns on the genetic and demographic aspects within these populations.

Birth Rate↗

PubMed1978

Consanguinity in multifactorial inheritance. Application to data on congenital glaucoma.

The increase of parental consanguinity in multifactorial inheritance is evaluated by calculating the expected incidence of affected children whose parents are first cousins, using several values, namely for condition frequency and heritability of liability. This increase is compared to the expected increase in recessive inheritance, when one or more loci are involved. The method is illustrated by examples of recessive and multifactorial conditions and applied, as a test of discrimination between different modes of inheritance, to data on congenital glaucoma.

Consanguinity↗

PubMed1980

Effects of parental consanguinity on mortality and reproductive function.

A study of consanguinity effects on mortality and fertility was performed. The original series consisted of families selected on the basis of the birth of at least one child with a congenital, monohybrid, autosomal recessive disease. Biologically related families were compared with unrelated ones, the latter group being used as a natural control group. The results are discussed.

Consanguinity↗

PubMed1991

Family distances as a measure of hidden consanguinity. A reappraisal.

We compared the family distances of patients with autosomal recessive disorders with those of a random control group and a matched control group. Only in the great-grandparental generation were weak-significant differences found. We also found that the family distances of persons with an urban origin were significantly larger than those of persons with a rural origin. In our study, family distance seems to be a more powerful measure of hidden consanguinity than the parental distance.

Chromosome Aberrations↗

PubMed2005

Autosomal recessive retinitis pigmentosa is associated with mutations in RP1 in three consanguineous Pakistani families.

PURPOSE: To localize and identify the gene and mutations causing autosomal recessive retinitis pigmentosa in three consanguineous Pakistani families. METHODS: Blood samples were collected and DNA was extracted. A genome-wide scan was performed by using 382 polymorphic microsatellite markers on genomic DNA from affected and unaffected family members, and lod scores were calculated. RESULTS: A genome-wide scan of 25 families gave an hlod = 4.53 with D8S260. Retinitis pigmentosa in all three families mapped to a 14.21-cM (21.19-Mb) region on chromosome 8 at q11, flanked by D8S532 and D8S260. This region harbors RP1, which is known to cause autosomal dominant retinitis pigmentosa. Sequencing of the coding exons of RP1 showed mutations in all three families: two single-base deletions, c.4703delA and c.5400delA, resulting in a frame shift, and a 4-bp insertion, c.1606insTGAA, all causing premature termination of the protein. All affected individuals in these families are homozygous for the mutations. Parents and siblings heterozygous for the mutant allele did not show any signs or symptoms of RP. CONCLUSIONS: These results provide strong evidence that mutations in RP1 can result in recessive as well as dominant retinitis pigmentosa. The findings suggest that truncation of RP1 before the BIF motif or within the terminal portion results in a simple loss of RP1 function, producing a recessive inheritance pattern. In contrast, disruption of RP1 within or immediately after the BIF domain may result in a protein with a deleterious effect and hence a dominant inheritance pattern.

Chromosomes, Human, Pair 8↗

PubMed1998

Dihydropteridine reductase deficiency in a large consanguineous Tunisian family: clinical, biochemical, and neuropathologic findings.

We report the case of a large consanguineous Tunisian family of seven siblings suffering from dihydropteridine reductase deficiency with either typical clinical, biochemical, or autopsy findings. Two cousins also were reported to have the same symptoms. This metabolic disorder is characterized by severe microcephaly, psychomotor regression, and progressive basal ganglia calcifications. Dihydropteridine reductase assay on samples collected from the two brothers still alive did not show measurable activity. The sister and four brothers died between the ages of 3 years and 7 years. A neuropathology study done on the sister showed diffuse demyelination throughout the white matter and spongy vacuolation in the subthalamic nuclei, the superior cerebellar peduncles and the tegmentum tracts of the brain stem. The anterointernal part of the putamen was completely necrotic with nearly total nerve cell loss. Abnormal vascular proliferation and calcification of the walls of small, medium, and large arteries and veins, as well as diffusely scattered pericapillary and isolated calcospherites, were seen in this necrotic region. We think that folate deficiency may be involved in the pathogenesis of the basal ganglia calcification.

Basal Ganglia Diseases↗

PubMed1992

Suspected synergism between consanguinity and familial aggregation in type 2 diabetes mellitus in Saudi Arabia.

A retrospective study of 210 cases of diabetes was carried out at King Khalid University Hospital diabetes clinic to delineate etiologic factors in non-insulin dependent diabetes mellitus (NIDDM). Standardised detailed questionnaires were administered to both cases and controls and the information sought included general demographics, dietary patterns, anthropometric values, family history, consanguinity and familial aggregation of Diabetes Mellitus (DM). Familial aggregation yielded an odds ratio of 6:2 which suggests a causal association with DM. A synergistic effect of familial aggregation was observed which needs to be further explored in future studies.

Adult↗

PubMed2024

A novel start-loss mutation of the SLC29A3 gene in a consanguineous family with H syndrome: clinical characteristics, in silico analysis and literature review.

BACKGROUND: The SLC29A3 gene, which encodes a nucleoside transporter protein, is primarily located in intracellular membranes. The mutations in this gene can give rise to various clinical manifestations, including H syndrome, dysosteosclerosis, Faisalabad histiocytosis, and pigmented hypertrichosis with insulin-dependent diabetes. The aim of this study is to present two Iranian patients with H syndrome and to describe a novel start-loss mutation in SLC29A3 gene. METHODS: In this study, we employed whole-exome sequencing (WES) as a method to identify genetic variations that contribute to the development of H syndrome in a 16-year-old girl and her 8-year-old brother. These siblings were part of an Iranian family with consanguineous parents. To confirmed the pathogenicity of the identified variant, we utilized in-silico tools and cross-referenced various databases to confirm its novelty. Additionally, we conducted a co-segregation study and verified the presence of the variant in the parents of the affected patients through Sanger sequencing. RESULTS: In our study, we identified a novel start-loss mutation (c.2T > A, p.Met1Lys) in the SLC29A3 gene, which was found in both of two patients. Co-segregation analysis using Sanger sequencing confirmed that this variant was inherited from the parents. To evaluate the potential pathogenicity and novelty of this mutation, we consulted various databases. Additionally, we employed bioinformatics tools to predict the three-dimensional structure of the mutant SLC29A3 protein. These analyses were conducted with the aim of providing valuable insights into the functional implications of the identified mutation on the structure and function of the SLC29A3 protein. CONCLUSION: Our study contributes to the expanding body of evidence supporting the association between mutations in the SLC29A3 gene and H syndrome. The molecular analysis of diseases related to SLC29A3 is crucial in understanding the range of variability and raising awareness of H syndrome, with the ultimate goal of facilitating early diagnosis and appropriate treatment. The discovery of this novel biallelic variant in the probands further underscores the significance of utilizing genetic testing approaches, such as WES, as dependable diagnostic tools for individuals with this particular condition.

Humans↗

PubMed2024

A novel frameshift variant in the TMPRSS3 gene causes nonsyndromic hearing loss in a consanguineous family.

BACKGROUND: Hearing Loss (HL) is the most common sensorineural condition in humans. Mutations in the TMPRSS3 gene (DNFB8/10 locus) have been linked to autosomal recessive non-syndromic hearing loss (ARNSHL). METHODS: Whole-exome sequencing (WES) was utilized to identify disease-causing variants in a proband from Iran with ARNSHL who presented clinically with sensorineural, bilateral, and prelingual HL. The pathogenicity and novelty of the identified variant were assessed using various databases. A co-segregation study was also performed to confirm the presence of the variant in the proband's parents. Additionally, the secondary and tertiary structures of the mutant TMPRSS3 protein were predicted using bioinformatics tools. Furthermore, a global mutational spectrum of TMPRSS3 was created and statistically analyzed. The Iranome database was also used to identify other putative mutations in the TMPRSS3 gene in the Iranian population. RESULTS: We identified a novel homozygous single nucleotide deletion in TMPRSS3 (c.297delA, p.Asp100ThrfsTer52) in the proband. This is the first report of this mutation in a patient with ARNSHL. Sanger sequencing confirmed that this variant co-segregated from the proband's parents. Bioinformatic tools classified this novel variant as likely pathogenic. Additionally, 49.55% of families with TMPRSS3-related HL patients were shown to have consanguinity, consistent with our study. The Iranome database also revealed the c.268G > A variant as a putative novel mutation in TMPRSS3. CONCLUSION: This research expanded the pool of evidence regarding the association between mutations in the TMPRSS3 gene and ARNSHL. The finding confirmed that a single nucleotide deletion caused HL in the proband, suggesting that genetic testing, such as WES, is a robust technique for diagnosing patients with this condition.

Humans↗

PubMed1994

Bipolar affective puerperal psychosis associated with consanguinity.

Most clinical and genetic evidence suggests that puerperal psychosis is closely related to bipolar affective disorder. During a linkage study of bipolar disorder we ascertained a British family in which puerperal psychosis was associated with consanguinity in three sisters. All three subjects had lifetime RDC diagnoses of bipolar I or manic disorder. An inbred brother also had bipolar I disorder. The only female member of the sibship to escape puerperal psychosis was outbred. These findings are consistent with several genetic models for bipolar disorder in this family. The most interesting possibility is a single major susceptibility locus of recessive effect. Under this assumption, the family could be used for homozygosity mapping to help localise the putative recessive locus. If other inbred families can be found in which the same putative recessive locus is operating, the power to localise the gene by homozygosity mapping would be greatly increased.

Bipolar Disorder↗

PubMed1998

Molecular characterization of pyruvate carboxylase deficiency in two consanguineous families.

Pyruvate carboxylase (PC) is a biotinylated mitochondrial enzyme that catalyzes the conversion of pyruvate to oxaloacetate. Children with inborn errors of PC metabolism have lactic acidosis, hypoglycemia, and mental retardation. The variable severity of the clinical phenotype is dependent on both genetic and environmental factors. Two consanguineous families with moderate forms of PC deficiency were characterized at the biochemical and molecular levels. In both families, the probands were found to have low PC activity (range, 2-25% of control) in blood lymphocytes and skin fibroblasts associated with either diminished or normal protein levels. In the first case, sequencing of patient-specific PC cDNA demonstrated a T to C substitution at nucleotide 434, which causes a valine to alanine change at amino acid residue 145. Direct sequencing of the parents showed that they are heterozygous for this mutation. In the second family, a brother and sister had mental retardation and episodes of severe lactic/ketoacidosis in early childhood. In these cases, a C to T substitution at nucleotide 1351 results in a cysteine for arginine substitution at amino acid residue 451; the parents were also found to be heterozygous for this mutation. In both families, no other mutations were found, and both substitutions occurred in relatively conserved amino acid residues. These mutations, located in the biotin carboxylase domain, provide a unique opportunity to analyze how natural occurring mutations affect PC function.

Base Sequence↗

PubMed2000

Autoimmune lymphoproliferative syndrome (ALPS) in a child from consanguineous parents: a dominant or recessive disease?

Autoimmune lymphoproliferative syndrome (ALPS) is characterized by autoimmune features and lymphoproliferations and is generally caused by defective Fas-mediated apoptosis. This report describes a child with clinical features of ALPS without detectable Fas expression on freshly isolated blood leukocytes. Detection of FAS transcripts via real-time quantitative PCR made a severe transcriptional defect unlikely. Sequencing of the FAS gene revealed a 20-nucleotide duplication in the last exon affecting the cytoplasmic signaling domain. The patient was homozygous for this mutation, whereas the consanguineous parents and the siblings were heterozygous. The patient reported here is a human homologue of the Fas-null mouse, inasmuch as she carries an autosomal homozygous mutation in the FAS gene and she shows the severe and accelerated ALPS phenotype. The heterozygous family members did not have the ALPS phenotype, indicating that the disease-causing FAS mutation in this family is autosomal recessive.

Autoimmune Diseases↗

PubMed2004

Mutations in the seipin and AGPAT2 genes clustering in consanguineous families with Berardinelli-Seip congenital lipodystrophy from two separate geographical regions of Brazil.

Berardinelli-Seip congenital lipodystrophy (BSCL) is characterized by a near total congenital absence of fat and predisposition to develop diabetes mellitus. In this study, we investigated the presence of mutations in the Seipin and 1-acylglycerol phosphate acyltransferase 2 (AGPAT2) genes in 32 affected subjects with BSCL from 17 consanguineous pedigrees living in two separate geographical regions, the northeastern and southeastern regions, of Brazil. All, except one, of the 22 BSCL subjects from 15 families living in the northeastern region were found to have a homozygous 669insA mutation in the Seipin gene. In contrast, all 10 BSCL subjects from two families living in the southeastern region were found to a have a homozygous 1036-bp deletion including exons 3 and 4 of AGPAT2. These results support genetic heterogeneity among BSCL patients in Brazil. Our finding of a single mutation in the Seipin and AGPAT2 genes in the pedigrees from the northeastern and southeastern regions, respectively, will be useful in genetic counseling of subjects from these large pedigrees from Brazil.

1-Acylglycerol-3-Phosphate O-Acyltransferase↗

PubMed1997

Genetic exclusion of 14 candidate genes in lipoatropic diabetes using linkage analysis in 10 consanguineous families.

Lipoatropic diabetes (LD) is a rare recessive autosomal disorder, mainly characterized by lipoatrophy with alterations in lipid metabolism and extreme insulin resistance. To identify molecular defects responsible for this disease, we tested the implication of 14 candidate genes coding for proteins involved either in insulin action, i.e. insulin receptor, insulin receptor substrate 1, insulin-like growth factor I receptor, diabetes-associated ras-like protein (Rad), and glycogen synthase, or in lipid metabolism, i.e. lipoprotein lipase; apolipoproteins CII, AII, and CIII; hepatic lipase; hormone-sensitive lipase; the beta 3-adrenergic receptor; leptin; and fatty acid-binding protein 2. To this end, haplotype and linkage analyses using genotyping with microsatellites in 10 consanguineous families provided us with powerful genetic tools. Our results show that in most families, lod scores at a null recombination fraction were less than -2. Haplotype analysis also argues against the involvement of these genes in LD. This implies that mutations in these genes are unlikely to make a major genetic contribution to LD.

Adolescent↗

PubMed1977

Adult onset autonomic dysfunction coexistent with familial dysautonomia in a consanguineous family.

A consanguineous family is described in which autonomic dysfunction developed in the father during adult life while the son had familial dysautonomia at birth. The father's condition is felt to be secondary to olivopontocerebellar atrophy. The concurrence in this family of an adult and a childhood form of dysautonomia may be an expression of the same genetic defect at different stages of development.

Adult↗

PubMed1992

Progressive supranuclear palsy-like syndrome in two siblings of a consanguineous marriage.

Two siblings of a consanguineous marriage showed identical clinical features consisting of supranuclear vertical ophthalmoplegia, bradykinesia, rigidity, stooped posture, pseudobulbar palsy, and dementia, all beginning in the sixth decade. There was no history of encephalitis or of exposure to known chemicals. L-Dopa therapy was only partially and temporarily effective. Autopsy of one patient revealed extensive neurofibrillary degeneration with prominent involvement of the limbic system. There were no senile plaques or Lewy bodies. Under electron microscopy, there were paired helical filaments as well as 15-nm-wide straight tubules. The diffuse appearance of neurofibrillary tangles, predominant in the limbic system, and familial occurrence are unusual in progressive supranuclear palsy; these cases may, therefore, constitute a different, distinctive clinicopathologic disease.

Consanguinity↗

PubMed1999

Consanguinity and recurrence risk of stillbirth and infant death.

OBJECTIVES: The aim of this study was to estimate the recurrence risk for stillbirth and infant death and compare results for offspring of first-cousin parents with results for offspring of unrelated parents. METHODS: The study population consisted of all single births with a previous sibling born in Norway between 1967 and 1994. Altogether, 629,888 births were to unrelated parents, and 3466 births were to parents who were first cousins. The risk of stillbirth and infant death was estimated for subsequent siblings contingent on parental consanguinity and survival of the previous sibling. RESULTS: For unrelated parents, the risk of early death (stillbirth plus infant death) for the subsequent sibling was 17 of 1000 if the previous child survived and 67 of 1000 if the previous child died before 1 year of age. For parents who were first cousins, the risk of early death for the subsequent sibling was 29 of 1000 if the previous child survived and 116 of 1000 if the previous child died. CONCLUSIONS: The risk of recurrence of stillbirth and infant death is higher for offspring of first-cousin parents compared with offspring of unrelated parents.

Adult↗