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A modification of Smith's method is described for deriving recurrence risks for multifactorial conditions when parents are related. Using cleft palate as an example, the possible increased risks caused by consanguinity are discussed.
PURPOSE: To determine the molecular diagnostic yield, variant spectrum, inheritance architecture, and influence of consanguinity on whole-exome sequencing outcomes in a South Indian retinitis pigmentosa (RP) cohort. DESIGN: Prospective, registry-based cohort study. SUBJECTS: A total of 113 affected participants were enrolled through the Aravind Registry for Inherited Diseases of the Eye, including 109 unrelated probands and 4 affected relatives from already represented families. Primary analyses were restricted to the 109 unrelated probands. METHODS: Whole-exome sequencing was performed using a clinical exome workflow. Variants were interpreted using American College of Medical Genetics and Genomics/Association for Molecular Pathology criteria and cases were categorized as solved, possibly solved, inconclusive, or unsolved using prespecified inheritance-aware rules. MAIN OUTCOME MEASURES: Molecular diagnostic yield, distribution of implicated genes and variant classes, inheritance architecture, and diagnostic yield stratified by consanguinity status. RESULTS: Among the 109 unrelated probands, mean age at testing was 39.3 ± 14.1 years and 58.7% were male. Whole-exome sequencing identified 186 distinct rare variants across 92 inherited retinal disease genes, including 26 pathogenic and 33 likely pathogenic variants. A molecular diagnosis was established in 50 of 109 probands (45.9%), including 42 solved and 8 possibly solved cases; 45 (41.3%) were inconclusive and 14 (12.8%) remained unsolved, including 4 (3.7%) in whom no candidate variant was identified. EYS, USH2A, and ADGRV1 were the most frequently implicated genes. Autosomal recessive (AR) disease predominated (44/50, 88.0%). Consanguineous AR cases were exclusively homozygous (17/17); notably, 68.0% of nonconsanguineous AR cases were also homozygous (P = 0.013). Diagnostic yield was higher in consanguineous probands (51.4% vs. 41.7%), without reaching significance. Recurrent alleles included an established South Asian founder variant (MFSD8 c.1361T>C) and candidate founder alleles in EYS (c.4321C>T) and ADGRV1 (c.14329C>T). CONCLUSIONS: Whole-exome sequencing established a molecular diagnosis in nearly half of this South Indian RP cohort and revealed a predominantly recessive, homozygosity-enriched architecture shaped by consanguinity. These findings define a region-specific variant landscape to support clinical interpretation, genetic counseling, and future trial enrollment in this underrepresented population. FINANCIAL DISCLOSURES: The authors have no proprietary or commercial interest in any materials discussed in this article.
The aim of this study was to determine the types, patterns, and frequencies of congenital anomalies among newborns of both consanguineous and nonconsanguineous parents in southern Iran. From 9526 consecutive pregnancies observed, 9623 newborns resulted (9431 singleton and 95 sets of multiple gestation). There were 7261 newborns from nonconsanguineous parents and 2362 (24.5%) babies from consanguineous marriages. Of the total pregnancies, 1.54% resulted in malformed children (1.53% of singleton and 2.1% of multiple gestations). The incidence of congenital abnormalities in newborns of nonconsanguineous parents was 1.66% as compared to 4.02% for newborns of the consanguineous group. Major and multiple malformations were found to be slightly more common in the consanguinous group. Prematurity, prenatal mortality rate, and congenital abnormalities were more common in the consanguineous group. Probably the closer the familial relationship of the parents, the greater the chances of congenital abnormalities.
PURPOSE: The genetic underpinning of neurodevelopmental disorders (NDDs) in diverse ethnic populations, especially those with high rates of consanguinity, remains largely unexplored. Here, we aim to elucidate genomic insight from 576 well-phenotyped and highly consanguineous (16%) NDD cohort. METHODS: We used chromosomal microarray (CMA; N:247), exome sequencing (ES; N:127), combined CMA and ES (N:202), and long-read genome sequencing to identify genetic etiology. Deep clinical multivariate data were coupled with genomic variants for stratification analysis. RESULTS: Genetic diagnosis rates were 17% with CMA, 29.92% with ES, and 37.13% with combined CMA and ES. Notably, children of consanguineous parents showed a significantly higher diagnostic yield (P < .01) compared to those from nonconsanguineous parents. Among the ES-identified pathogenic variants, 36.19% (38/105) were novel, implicating 35 unique genes. Long-read sequencing of seizure participants unresolved by combined test identified expanded FMR1 trinucleotide repeats. Additionally, we identified 2 recurrent X-linked variants in the G6PD in 3.65% (12/329) of NDD participants. These variants were absent in large-population control cohorts and cohort comprising neurodevelopmental and neuropsychiatric populations of European descendants, indicating a possible associated risk factor potentially resulting from ancient genetic drift. CONCLUSION: This study unveils unique clinical and genomic insights from a consanguinity rich Bangladeshi NDD cohort.
PURPOSE: Genetic testing in consanguineous families advances the general comprehension of pathophysiological pathways. However, short stature (SS) genetics remain unexplored in a defined consanguineous cohort. This study examines a unique pediatric cohort from Sulaimani, Iraq, aiming to inspire a genetic testing algorithm for similar populations. METHODS: Among 280 SS referrals from 2018-2020, 64 children met inclusion criteria (from consanguineous families; height ≤ -2.25 SD), 51 provided informed consent (30 females; 31 syndromic SS) and underwent investigation, primarily via exome sequencing. Prioritized variants were evaluated by the American College of Medical Genetics and Genomics standards. A comparative analysis was conducted by juxtaposing our findings against published gene panels for SS. RESULTS: A genetic cause of SS was elucidated in 31 of 51 (61%) participants. Pathogenic variants were found in genes involved in the GH-IGF-1 axis (GHR and SOX3), thyroid axis (TSHR), growth plate (CTSK, COL1A2, COL10A1, DYM, FN1, LTBP3, MMP13, NPR2, and SHOX), signal transduction (PTPN11), DNA/RNA replication (DNAJC21, GZF1, and LIG4), cytoskeletal structure (CCDC8, FLNA, and PCNT), transmembrane transport (SLC34A3 and SLC7A7), enzyme coding (CYP27B1, GALNS, and GNPTG), and ciliogenesis (CFAP410). Two additional participants had Silver-Russell syndrome and 1 had del22q.11.21. Syndromic SS was predictive in identifying a monogenic condition. Using a gene panel would yield positive results in only 10% to 33% of cases. CONCLUSION: A tailored testing strategy is essential to increase diagnostic yield in children with SS from consanguineous populations.
The influence of the increase of the degree of homozygosity, obtained by successive consanguine cross-breeding, on the mean weights and the variability of the weights of twelve muscles of the Japanese quail (Coturnix c. japonica) was studied in four generations of females and two generations of males. It was found that the mean weights of the twelve muscles in both sexes showed a progressive reduction in the consecutive generations of consanguine crosses, this reduction being more marked in the males than in the females. These results support the hypotheses of Haldane and Lerner that heterozygotes are at an advantage, having a more active metabolism and a greater rate of growth, because their richer biochemical system and greater number of alleles coding the enzymes enables them to benefit from their environment to a greater extent and within wider limits. The rates of decrease vary from one muscle to the other within the limits of 5.3 and 16.6%. For certain muscles there are also notable differences between males and females. Contrary to the hypothesis that could be formed at first sight, the variability in weight increases considerably, in almost all cases, when the degree of homozygosity increases. Here again quite considerable differences are found in the evolution of the variability with the degree of homozygosity, from one muscle to the other and also between the two sexes. Comparison of the mean weight of the left and right elements of the bilateral muscles shows no significant preponderance. It was found, however, that slight asymmetries observed in the different groups of different consanguinity tend to be in the same direction for a given muscle. The variability of the weights of the left and right elements does not seem to be influenced by the degree of homozygosity in the females; in the males, however, an increase in homozygosity increases the variability of the weights of the left and right elements in certain cases. The mean degree of humidity and the variability of the ratio wet weight/dry weight are not changed significantly by the degree of consanguinity in females. In the males, the variability in the degree of humidity is less in heterozygotes, an indication of their better capacity for homeostatic regulation. The reduction in the mean weights and the increase in variability as the degree of homozygosity increases shows the importance of the advantage of heterozygotes, which has a bearing on theories of the genetics of populations and their application in rearing, and particularly to selection techniques.
BACKGROUND AND OBJECTIVE: Autosomal recessive genetic disorders pose significant health challenges in regions where consanguineous marriages are prevalent. The utilization of exome sequencing as a frequently employed methodology has enabled a clear delineation of diagnostic efficacy and mode of inheritance within multiplex consanguineous families. However, these aspects remain less elucidated within simplex families. METHODS: In this study involving 12 unrelated simplex Iranian families presenting syndromic autism, we conducted singleton exome sequencing. The identified genetic variants were validated using Sanger sequencing, and for the missense variants in FOXG1 and DMD, 3D protein structure modeling was carried out to substantiate their pathogenicity. To examine the expression patterns of the candidate genes in the fetal brain, adult brain, and muscle, RT-qPCR was employed. RESULTS: In four families, we detected an autosomal dominant gene (FOXG1), an autosomal recessive gene (CHKB), and two X-linked autism genes (IQSEC2 and DMD), indicating diverse inheritance patterns. In the remaining eight families, we were unable to identify any disease-associated genes. As a result, our variant detection rate stood at 33.3% (4/12), surpassing rates reported in similar studies of smaller cohorts. Among the four newly identified coding variants, three are de novo (heterozygous variant p.Trp546Ter in IQSEC2, heterozygous variant p.Ala188Glu in FOXG1, and hemizygous variant p.Leu211Met in DMD), while the homozygous variant p.Glu128Ter in CHKB was inherited from both healthy heterozygous parents. 3D protein structure modeling was carried out for the missense variants in FOXG1 and DMD, which predicted steric hindrance and spatial inhibition, respectively, supporting the pathogenicity of these human mutants. Additionally, the nonsense variant in CHKB is anticipated to influence its dimerization - crucial for choline kinase function - and the nonsense variant in IQSEC2 is predicted to eliminate three functional domains. Consequently, these distinct variants found in four unrelated individuals with autism are likely indicative of loss-of-function mutations. CONCLUSIONS: In our two syndromic autism families, we discovered variants in two muscular dystrophy genes, DMD and CHKB. Given that DMD and CHKB are recognized for their participation in the non-cognitive manifestations of muscular dystrophy, it indicates that some genes transcend the boundary of apparently unrelated clinical categories, thereby establishing a novel connection between ASD and muscular dystrophy. Our findings also shed light on the complex inheritance patterns observed in Iranian consanguineous simplex families and emphasize the connection between autism spectrum disorder and muscular dystrophy. This underscores a likely genetic convergence between neurodevelopmental and neuromuscular disorders.
BACKGROUND: Intellectual disability represents a heterogeneous group of neurodevelopmental disorders marked by significant impairments in intellectual functioning and adaptive behavior. Among the various causes, genetic factors play a major role, with autosomal recessive intellectual disability (ARID) constituting a genetically diverse subgroup. ARID is prevalent in consanguineous families and arises from homozygous mutations that disrupt critical genes involved in brain development and function. OBJECTIVE: This study aimed to identify disease-causing genetic variants responsible for ARID in a consanguineous Pakistani family and to evaluate the structural and functional impact of a novel variant identified in GAD1 through protein modeling. METHODS: A consanguineous family affected with intellectual disability was enrolled. Whole-exome sequencing was performed on an affected individual, followed by bioinformatics analysis including alignment to the GRCh38 reference genome, variant calling, and annotation. Variants were filtered based on rarity, predicted functional impact, and autosomal recessive inheritance pattern. Candidate variants were validated and assessed by Sanger sequencing and segregation analysis. Protein modeling was performed to evaluate the structural impact of the identified variant. RESULTS: A novel homozygous missense variant NM_000817:c.1700G>A;p.Arg567Gln in GAD1 was identified. Segregation analysis confirmed co-segregation of the variant with the affected phenotype. Protein modeling suggested that the variant may disrupt GAD1 enzymatic function involved in gamma-aminobutyric acid synthesis. CONCLUSION: This study emphasizes the significance of genetic investigation in familial cases and the crucial role that GAD1 mutations play in neurodevelopmental disorders with intellectual disability. The results advance the knowledge of molecular causes of ARID and broaden the mutational range.
The incidence of consanguineous marriages is very high in the Pattusali population. First cousin marriages are preferred mostly. The consanguinity effects obtained in this population are also mostly confined to these marriages only. The inbreeding coefficient for the population is 0.02997. The consanguinity on fertility, mortality and morbidity are discussed in the paper.
Glucose-6-phosphatase catalytic subunit 3 deficiency, also known as Dursun syndrome, is a rare autosomal recessive disorder characterized by severe congenital neutropenia and variable multisystem malformations, particularly affecting the cardiovascular system. Most reported cases have been identified postnatally, following infectious or hematologic complications. Prenatal identification remains exceptionally rare. We describe the case of a fetus from consanguineous parents with a history of multiple neonatal deaths. Serial prenatal imaging demonstrated progressive fetal growth restriction, cardiomegaly with biventricular hypertrophy, significant tricuspid regurgitation, right-sided cardiac dominance, right atrial enlargement, ventriculomegaly, and evolving craniofacial dysmorphism. Whole-exome sequencing revealed a homozygous nonsense variant in G6PC3 (NM_138387.3:c.481C > T; p.(Arg161Ter)), confirming that both parents were heterozygous carriers. Postnatally, the neonate developed severe neutropenia, complex right-sided cardiac outflow obstruction physiology, and refractory cardiorespiratory failure, leading to death on day 4 of life. This report expands the prenatal phenotypic spectrum of glucose-6-phosphatase catalytic subunit 3 deficiency and emphasizes the importance of considering this diagnosis in fetuses presenting with cardiomyopathy, dysmorphic features, fetal growth restriction, and parental consanguinity. Early molecular diagnosis enables accurate counseling, informed reproductive planning, and consideration of preconception or early prenatal genomic testing in high-risk families.
The effects of social class on migration distances and on the frequency of consanguineous marriages in Errazu, a Pyrenean village in Navarre, Spain, have been studied using data from parish records of baptisms and marriages, 1850-1910, and the census data for the year 1897. Migration distances are greater for tenants than for land-owners. Mean marital distances are not significantly different for the two social classes, but the movement of tenant families during married life results in significantly different parent-offspring distances for the two classes, at the 0.001 level for fathers and at the 0.002 level for mothers, by a t-test. Consanguineous marriages, up to and including third cousin marriages, are more frequent among land-owners (16.3 per cent) than among tenants (3.7 per cent). These frequencies are consistent with estimates based on the demographic characteristics of the population. Some implications of these results are discussed with reference to the findings of communities elsewhere in Europe and studies of communities in Japan. The implications of variation in the social class composition of populations with population density, for pedigree inbreeding values, are also considered.
The sex ratio among acheiropods is shown to be not significantly different from the sex ratio among their normal sibs, as well as among other segments of the family (parental sibships, cousin sibships and other sibships). The frequency of consanguineous marriages among the parents of acheiropods (82%) is one of the highest thus far reported among parents of individuals affected with rare autosomal recessive anomalies or diseases. No evidence was found of any overall positive or negative birth order effect on the incidence of acheiropodia. These results further strengthen the hypothesis of a simple genetic mechanism for acheiropodia, namely autosomal recessive inheritance, without any detectable complication as regards sex ratio, consanguinity and birth order. Although the family size from heterozygous parents (producing at least one acheiropod) was twice as large as family sizes in other segments of the families (8 against 4), we have at present no evidence to support either heterozygous advantage or reproductive compensation.
The study was carried out in the Gurage area of Ethiopia, where 53 household contacts of lepromatous patients, 37 household contacts of tuberculoid patients, and 91 control persons were examined with the lymphocyte transformation test (LTT) for their responses to whole and sonicated antigen preparation from M. leprae to BCG, M. avium, M. gordonae and phytohemagglutinin. The potential influence of host factors, namely the state of consanguinity with the leprosy patient, sex and age on the LTT responses was evaluated. In the 35 household contacts of "active," i.e., highly bacilliferous, lepromatous patients, consanguinity with a lepromatous patient was not associated with a significant depression of the LTT responses to M. leprae antigens. Male household contacts of active lepromatous patients showed significantly greater LTT responses to M. leprae antigens than female household contacts. Possible confounding factors for this finding are discussed. Sensitization of M. leprae antigens was present already in a high proportion of the 6 to 14 year old household contacts of active lepromatous patients, which was the youngest age group examined in our study. No significant results were found in any of the other patient contact groups with regard to the host factors examined.
Osteopetrosis, a group of highly heterogeneous genetic bone disorders, is characterized by deafness, increased bone density, hepatosplenomegaly, pancytopenia and intellectual disability. Osteopetrosis can be divided into three subtypes: autosomal recessive osteopetrosis (ARO), intermediate autosomal recessive osteopetrosis (IARO), and autosomal dominant osteopetrosis (ADO). CLCN7 has been reported to be the most common gene responsible for the ADO-II subtype. In this study, a novel variant, c.175dupA (p.Met59Asnfs*8), of CLCN7 was identified in a Chinese Han consanguineous family with suspected ADO-II. The proband was homozygous for the p.Met59Asnfs*8 variant and exhibited multiple severe phenotypes, including deafness, short stature, brittle bones, optic atrophy, hepatosplenomegaly, intellectual disability, cleft palate and recurrent infection. However, except for the mother of the proband, who presented a series of clinical phenotypes caused by bone marrow failure, all the other family members who were heterozygous had no obvious abnormal phenotypes. Our study suggested that the novel variant p.Met59Asnfs*8 in CLCN7 was very likely pathogenic factor in our suspected ADO-II family. The phenotypes of heterozygous carriers may be affected by incomplete penetrance. Loss of function of CLCN7 caused by nonsense-mediated mRNA decay (NMD) due to the frameshift variant was likely the underlying pathogenic mechanism. This study broadened the mutation spectrum of CLCN7, provided a foundation for timely and effective clinical intervention for related diseases, and demonstrates the importance of genetic counselling.
3M syndrome is a rare genetic familial disorder characterized by short stature, growth retardation, facial dysmorphism, skeletal abnormalities, fleshy protruding heels, and normal intelligence, caused by mutations in the CUL7, OBSL1 and CCDC8 genes. In the present study, a novel homozygous missense variant of CUL7 (NP_001161842.1, c.4493T > C, p.L1498P) has been identified in a consanguineous Pakistani family by whole exome sequencing. In silico structural evaluation, molecular docking and simulation studies of mutant CUL7 provides substantial evidence about its crucial role in the progression of discussed ailment. The newly discovered variant significantly altered the protein's three dimensional structure, leading to abnormal interaction with binding proteins. This computational and experimental investigation provides useful information to drug developers for the synthesis of novel therapeutics against the discussed ailment.Communicated by Ramaswamy H. Sarma.
A correction is made to an expression given by Jacquard (1968, 1972a,b) for the genotypic distribution of a relative of a given homozygote when consanguinity is present. The correction will necessarily be small either if the allele present in the given homozygote has a frequency of near unity, or if the coefficient of inbreeding of the given homozygote is small.
A case of cerebro-hepato-renal syndrome with some unusual features is reported. The neuropathological findings are described in detail. Electronmicroscopy showed astrocytes in the demyelinated areas of the brain to contain granules composed of laminated osmiophilic material. These structures could be abnormal mitochondria. The parental consanguinity in this case would further support an autosomal recessive mode of inheritance.
We describe a female infant with the cervical vertebral fusion (Klippel-Feil) syndrome whom we recognized at birth because of her short neck, restriction of cervical movement, and low posterior hairline. X-ray examination showed anomalies of C1, and between C2-3 and C3-4; thus, we classified her as type II, with variable cervical fusion. At 24 months she was small and manifested hearing deficiency. The mother and father were consanguineous with five common ancestors four generations ago, which resulted in a coefficient of inbreeding equivalent to a second cousin relationship. The parents and grandparents were phenotypically normal, and the parents were radiologically normal. This form of the syndrome has previously been said to be autosomal dominant. Our conclusion of determination by a single autosomal recessive gene is evidence of genetic heterogeneity.