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Pakistan has a significant occurrence of both consanguineous marriages and intimate partner violence (IPV), which may be interlinked. The practice of consanguineous marriages could potentially influence women to rationalize and accept instances of IPV. Such attitudes perpetuate a culture of violence against women, creating difficulties for victims to reject or escape from it. Pakistan has high prevalence rate of consanguineous marriages and IPV. However, no research has been done to explain the difference in acceptance of IPV between women in consanguineous and non-consanguineous marriages. This study used Pakistan Demographic and Health Survey data and applied association tests, logistic regression, and the Fairlie decomposition analysis. The Fairlie decomposition helps us identify the relative contribution of different socioeconomic factors in the inequalities in IPV between the two types of marriages. Five dimensions of wife-beating justification are used as outcome variables. Age, education, and empowerment of women, husband education, woman witness parental violence, region, place of residence, and household wealth status are used as independent variables. The logistic regression results indicated that women in consanguineous marriages of younger age and who witnessed parental violence are more likely to justify wife-beating than those who belong to wealthy households and enjoy more empowerment. Compared to the Punjab province, women residing in Sindh and Baluchistan are less likely and in the Khyber Pakhtunkhwa province are more likely to justify wife-beating. The Fairlie decomposition analysis shows that household wealth status, woman education, and empowerment are the main contributors in explaining the gap between the wife-beating justification of the two groups. The IPV gap can be reduced up to 77% if the distribution of women in different wealth quantiles of the consanguineous marriage group is identical to the non-consanguineous marriage group. Furthermore, woman education level is the second highest contributor. Consanguineous marriages are a prevalent cultural practice in Pakistan and are associated with several negative health and social outcomes. Addressing this issue requires a sustained and comprehensive effort by the government, civil society, and international partners, with a particular focus on women from poor households with less education. [ABSTRACT FROM AUTHOR]

Background: Preconception expanded carrier screening (ECS) is a genetic test that enables the identification of at-risk carriers of recessive disorders by screening for up to hundreds of genes. Next-generation sequencing (NGS) development has paved the way for its integration into ECS. This study aims to identify the carrier genetic status of couples experiencing or anticipating conception challenges through NGS-based ECS and to gain an overview of the rare genetic disorders in a population with increased consanguinity. Methods: Thirty couples who presented to the Genetic Disease Clinic between 2015 and 2024 with failed reproductive outcomes or with a positive personal or family history of genetic disorders and underwent ECS were included and retrospectively analyzed. Results: Fifty-four individuals (90.00%) were found to carry at least one variant of 95 identified genes, totaling 174 variants. Six individuals (10.00%) tested negative for any variant. Seven individuals had one variant (11.67%), 13 had two variants (21.67%), and 34 had 3 or more variants (56.67%). The most common variants identified were of HBA, HBB, CYP21A2, and G6PD genes. Most of the detected variants were unknown or unexpected (n = 143, 82.18%). Eight couples carried two or more variants in common. Consanguinity was reported in 14 couples (46.67%). Conclusions: Preconception ECS is crucial for reproductive planning, permitting couples to evaluate their combined genetic risks and make informed decisions, reducing the chance of having children with genetic disorders. [ABSTRACT FROM AUTHOR]

Background: Several studies pointed out the importance of genetic risk factors such as parental consanguinity (PC) and familial multiple sclerosis (FMS) in the risk of MS. This study aimed to investigate the PC and FMS among people with MS (pwMS) in Isfahan, Iran. Methods: This case–control study was conducted on pwMS from the MS clinic of Kashani Hospital, Isfahan, Iran, in October 2023. A group of healthy controls (HC) were also recruited. Data on demographic and clinical characteristics and history of PC and FMS were collected from participants. The relationships between PC, FMS, and developing MS were assessed using multinomial logistic regression analysis. The odds ratio (OR) with a 95% confidence interval (CI) was computed. Results: A total number of 4264 pwMS and 400 HCs were included. The prevalence of PC and FMS among pwMS were 29.3% and 24%, respectively. Multinomial logistic regression adjusted for age and sex indicated that the odds of developing MS were significantly associated with a history of PC (OR = 3.03, 95% CI 2.23 to 4.13, p < 0.001) and FMS (OR = 5.42, 95% CI 3.51 to 8.38, p < 0.001). Conclusion: PC and FMS can increase the risk of developing MS. They should be considered along with other risk factors for developing MS. A comprehensive conclusion requires further research. [ABSTRACT FROM AUTHOR]

Introduction and aim: Cystinuria represents a rare cause of urolithiasis, accounting for 1% of all cases. However, it poses unique challenges in diagnosis and management. This study aimed to examine the challenges of managing cystine stones from the perspective of cystinuria patients. Methods: Following ethical approval, we reviewed the medical records of cystine stone patients treated at four tertiary centers from 2016 to 2021 and surveyed them on their perceptions of cystinuria. It included questions about demographic characteristics, herbal treatments, pain management, online engagement, disease outcomes, and cystinuria-related fears. Results: The study included 28 adults with cystinuria nephrolithiasis, with a mean age of 30.5 years. Of these, 78.6% had consanguineous parents, and the first stone episode occurred at a mean of 14.82 years age. Family history of Cystinuria was encountered in 82.1%. Cystinuria was diagnosed after a mean of 6.43 years from the first stone episode, and stone analysis was performed in 22/28 after a mean of 3.86 years from the first stone episode. Only 17 patients (60.8%) underwent metabolic evaluation for kidney stones. Regarding non-surgical treatments, 13 (46.5%) patients received alkalinization medication, and only 10 (35.7%) were prescribed chelating agent therapy. Additionally, 50% of patients took herbal remedies. Conclusion: The diagnosis of cystinuria is often delayed, leading to a delay in receiving medical treatment (alkalinization and chelating agents) and poor health education and counseling. Thus, referring cystinuria patients to tertiary hospitals and providing a multidisciplinary approach might decrease the morbidity of the disease and enhance their well-being. [ABSTRACT FROM AUTHOR]

Preconception and prenatal genetic counseling is a well-established means of risk assessment in many parts of the world, and in recent years, an emerging concept in India. Likelihood of an offspring having autosomal recessive disorder increases based on the degree of consanguinity. Hence, genetic testing of the couple for the identification of carrier status for disease-causing variants is crucial. The purpose of this study is to understand the frequency of genetic abnormalities in consanguineous marriages by using a comprehensive genetic testing algorithm where in karyotyping, FISH, exome sequencing and microarray are used sequentially to determine the genetic etiology based on the clinical presentation and to evaluate the need and benefits of preconceptional and prenatal genetic counseling. This retrospective study includes 66 couples having consanguinity referred for genetic counseling and testing. Of the 66 couples, 58 underwent comprehensive genetic testing which included Karyotyping, Fluorescence in Situ Hybridization (FISH), Microarray and Exome sequencing based on their clinical presentation. The analyses revealed a genetic abnormality in approximately 31% and chromosomal polymorphic variations & variants of uncertain significance in 17% of the couples. Counseling in these couples helped in identifying the carrier status and enabled them to take an informed decision in subsequent pregnancies. These findings reiterate the acute need for preconception and prenatal genetic counseling services in India. [ABSTRACT FROM AUTHOR]

Objectives: This study was aimed to report the prevalence-pattern of hereditary and congenital anomalies (CA) in general population of Balochistan province of Pakistan, and to elucidate the familial/sporadic presentations and parental consanguinity of CA. Methods: In a multi-center cross-sectional study, patients with CA were ascertained from various district hospitals and public places throughout Balochistan from 2019 to 2023. Online Mendelian Inheritance in Man (OMIM) and International Classification of Diseases (ICD-10) databases were utilized for uniformity in classification. Descriptive statistics was employed. Results: A cohort of 1185 independent patients diagnosed with CA was recruited and the index males were 71%. The CA were classified into nine major and 118 minor entities. In the major categories, neurological disorders had the highest prevalence (n=317; 27%), followed by limb defects (n=161; 14%), blood-heart defects (n=159; 13%), neuromuscular anomalies (n=156; 13%), sensorineural/ear defects (n=140; 12%), eye/visual impairments (n=90; 8%), musculoskeletal defects (n=83; 7%), ectodermal defects (n=31; 3%), and others (48; 4%). Sixty one percent CA were sporadic in nature and 39% were familial; and parental consanguinity was observed in 51% cases. Several rare CA were witnessed. Conclusions: High preponderance of sporadic presentations in neuromuscular anomalies and musculoskeletal defects and low incidence of parental consanguinity in ectodermal defects and musculoskeletal defects may depict a significant etiological role of non-genetic/environmental factors such as prenatal exposures and maternal conditions. In this context, it is important to increase health education, enhance antenatal and perinatal care, and strengthen the health-care system in Balochistan to reduce the burden of CA. [ABSTRACT FROM AUTHOR]

The distribution of fitness effects of new mutations plays a central role in evolutionary biology. Estimates of the distribution of fitness effect from experimental mutation accumulation lines are compromised by the complete linkage disequilibrium between mutations in different lines. To reduce the linkage disequilibrium, we constructed 2 sets of recombinant inbred lines from a cross of 2 Caenorhabditis elegans mutation accumulation lines. One set of lines ("RIAILs") was intercrossed for 10 generations prior to 10 generations of selfing; the second set of lines ("RILs") omitted the intercrossing. Residual linkage disequilibrium in the RIAILs is much less than in the RILs, which affects the inferred distribution of fitness effect when the sets of lines are analyzed separately. The best-fit model estimated from all lines (RIAILs + RILs) infers a large fraction of mutations with positive effects (∼40%); models that constrain mutations to have negative effects fit much worse. The conclusion is the same using only the RILs. For the RIAILs, however, models that constrain mutations to have negative effects fit nearly as well as models that allow positive effects. When mutations in high linkage disequilibrium are pooled into haplotypes, the inferred distribution of fitness effect becomes increasingly negative-skewed and leptokurtic. We conclude that the conventional wisdom—most mutations have effects near 0, a handful of mutations have effects that are substantially negative, and mutations with positive effects are very rare—is likely correct, and that unless it can be shown otherwise, estimates of the distribution of fitness effect that infer a substantial fraction of mutations with positive effects are likely confounded by linkage disequilibrium. [ABSTRACT FROM AUTHOR]

Thiamine-responsive megaloblastic anemia (TRMA) syndrome is a rare syndrome with an autosomal recessive manner that develops due to a mutation in the SLC19A2gene. SLC19A2 encodes the highaffinity thiamine transport protein 1 (THTR1), which mediates the active transport of thiamine. The classical triad consists of megaloblastic anemia, sensorineural hearing loss, and non-autoimmune diabetes. Apart from this, ophthalmological, cardiological, and neurological findings have also been described. We present a case of thiamine-responsive megaloblastic anemia (TRMA) syndrome diagnosed in an adult with a novel mutation in the SLC19A2 gene. This 38-year-old female patient, a third child from a consanguineous marriage, presented with the classic TRMA triad: sensorineural deafness, megaloblastic anemia, and autoimmune diabetes. Starting thiamine treatment is essential in reducing the devel opmen t/pro gress ion of some complications; it is crucial to increase awareness of the disease and make an early diagnosis. [ABSTRACT FROM AUTHOR]

Introduction: Neonatal diabetes mellitus (NDM) is a rare non‐immunological monogenic disorder characterized by hyperglycemic conditions primarily occurring within the first 6 months of life. The majority of cases are attributed to pathogenic variants in genes affecting beta‐cell survival, insulin regulation, and secretion. This study aims to investigate the genetic landscape of NDM in Iran. Methods: We recruited a total of 135 patients who were initially diagnosed with diabetes at <12 months of age in Iran and referred to pediatric endocrinology clinics across the country. These patients underwent genetic diagnostic tests conducted by the Exeter Molecular Genetics Laboratory in the UK. The pathogenic variants identified were sorted and described based on type, pathogenicity (according to ACMG/AMP criteria), novelty, and the affected protein domain. Results: Genetic defects were identified in 93 probands, presenting various pathogenic abnormalities associated with NDM and its associated syndromes. 76% of the patients were born as a result of consanguineous marriage, and a familial history of diabetes was found in 43% of the cases. A total of 58 distinct variants in 14 different genes were discovered, including 20 variants reported for the first time. Causative variants were most frequently identified in EIF2AK3, KCNJ11, and ABCC8, respectively. Notably, EIF2AK3 and ABCC8 exhibited the highest number of novel variants. Discussion: These findings provide valuable insights into the genetic landscape of NDM in the Iranian population and contribute to the knowledge of novel pathogenic variants within known causative genes. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) heritability is estimated to be around 70–80%. Yet, much of it remains to be explained. Studying transmission patterns may help in understanding other factors contributing to the development of AD. Objective: In this study, we aimed to search for evidence of autosomal recessive or X- and Y-linked inheritance of risk factors in a large cohort of Portuguese AD patients. Methods: We collected family history from patients with AD and cognitively healthy controls over 75 years of age. We compared the proportions of maternal and paternal history in male and female patients and controls (to search for evidence of X-linked and Y-linked inherited risk factors). We compared the risk of developing AD depending on parents' birthplace (same vs. different), as a proxy of remote consanguinity. We performed linear regressions to study the association of these variables with different endophenotypes. Results: We included 3090 participants, 2183 cognitively healthy controls and 907 patients with AD. Men whose mother had dementia have increased odds of developing AD comparing to women whose mother had dementia. In female patients with a CSF biomarker-supported diagnosis of AD, paternal history of dementia is associated with increased CSF phosphorylated Tau levels. People whose parents are from the same town have higher risk of dementia. In multivariate analysis, this proxy is associated with a lower age of onset and higher CSF phosphorylated tau. Conclusions: Our study gives evidence supporting an increased risk of developing AD associated with an X-linked inheritance pattern and remote consanguinity. [ABSTRACT FROM AUTHOR]

Fragile X syndrome is a genetic condition causing a range of developmental problems, with males more severely affected compared to female patients. The main features include a long and narrow face, large ears, and a prominent jaw and forehead. Males develop enlarged testicles after puberty, and carrier females are expected to show fragile X-associated primary ovarian insufficiency (FXPOI). Fragile X Syndrome (FXS) was suspected in a consanguineous family referred to a Medical Genetics center because of a family history of intellectual disability and primary ovarian insufficiency in their small village population. The cytosine guanine guanine (CGG) repeat expansion of the FMRI gene in the 65-year-old proband was amplified and then analyzed by Gene Marker software. The female proband showed two expanded alleles, including one full mutation allele and one premutation allele with an accurate size of 74 (CGG) repeats. Despite having two mutant FMRI alleles and manifesting some symptoms of FXS, she was fertile. Consanguineous marriages and, in more unfavorable conditions, marrying Fragile X-affected or premutation-carrying males with female carriers is not uncommon in such genetically isolated populations. Therefore, the need for Fragile X syndrome examination in suspected patients with similar features and screening their relatives is highly emphasized [ABSTRACT FROM AUTHOR]

We hypothesized that consanguineous marriage will remain a risk factor for pregnancy outcome and offspring mortality, but the development in demographic, socioeconomic conditions and increased utilization of maternal and child health care services during postglobalization era would work as a buffer in the reduction of child mortality rates. Data fromNational Family Health Surveys 4(2015–2016) and 5(2019–2021) were pooled and used for the analysis. Binary logistic regression and Cox proportional hazard regression models were used to examine the effects of close (CC) and distant (DC) consanguinity on spontaneous abortion, stillbirth, neonatal mortality, post-neonatal, and child mortality respectively compared to non-consanguinity (NC). The final model showed that the risk of spontaneous abortion (both CC and DC, p < 0.001) and neonatal mortality (DC, p < 0.001) were significantly higher compared to NC. No significant association was found between consanguinity and child mortality. We conclude that the endogenous effect of consanguinity still pose a serious challenge to the survival of fetus and new born; but exogenous effect reduces the risk of child death. We propose to incorporate socially entrenched practice of consanguinity explicitly into Mosley and Chen's (1984) framework for the aid in understanding child survival in developing countries. [ABSTRACT FROM AUTHOR]

In the Central Plains of China during the Zhou Dynasty (1046-256 BCE), the social hierarchy gradually solidified, accompanied by frequent wars and the phenomena of multicultural and multi-ethnic integration. These social phenomena collectively influenced the population's genetic structure at that time. However, our understanding of the genetic history of this period remains largely unknown owing to limited ancient DNA studies. In this study, we successfully obtained 11 ancient genomes from the Guanzhuang site during the Zhou Dynasty on the central plain of China. Our findings revealed remarkable genetic continuity with the Neolithic populations of the Yellow River Basin and emphasized genetic diversity through the analysis of uniparental genetic markers. Population structure analysis further confirmed the genetic similarity between the Guanzhuang population and ancient populations of the Yellow River Basin and indicated genetic exchanges with ancient populations from surrounding regions. Intriguingly, signs of inbreeding within the Guanzhuang community cast doubt on the stringent enforcement of the contemporary marital regulations against consanguineous marriages within the same surname or clan. These revelations significantly enhance our insight into the complex interplay of ancient demography and societal organization, concurrently presenting a genetic perspective to view the complex evolution of Chinese civilization's multiethnic. [ABSTRACT FROM AUTHOR]

Cystic fibrosis (CF) is a genetic monogenic disorder inherited in an autosomal recessive manner, marked by persistent airway infections in the endobronchial region. This condition leads to the gradual development of bronchiectasis and, ultimately, respiratory failure, emerging as the primary cause of mortality in individuals diagnosed with CF. Diagnosis is done depending on the patient's symptoms and lung radiological findings like chest X‐rays and CTs. In younger patients and children, diagnosis becomes difficult due to overlapping symptoms with other diseases such as CF which is a rare genetic disease in our population. Diagnosis of CF usually relies on characteristic symptoms, a family history of CF, and an abnormal sweat chloride test, but in children, low sweat production during testing leads to false negative results. In this case report, a suspected patient with ambiguous respiratory symptoms underwent a comprehensive investigation revealing elevated CRP levels, TLC, and characteristic pulmonary manifestations on chest X‐ray, suggesting cystic fibrosis. Despite negative sweat chloride tests, the patient was analysed for potential candidate SNPs and was also tested for potential CFTR mutations to rule out CF, genetic analysis confirmed the diagnosis. Genetic testing plays a crucial role in diagnosing cystic fibrosis, even when traditional tests are inconclusive. Specific mutations like Δ508 deletion and rs213950 guide personalized treatment. Consanguinity and family history highlight genetic predisposition, while environmental factors may influence symptom onset. Further research is needed to understand these complexities and improve diagnostic and treatment approaches. [ABSTRACT FROM AUTHOR]

Aim Method Results Interpretation To determine the proportion of persons with cerebral palsy (CP) with major congenital anomalies, factors associated with the presence of anomalies, body systems involved, potential contribution to CP aetiology, and causal pathway subgroups implicated.This population‐based, observational study involved a cohort of 2238 persons born in one Australian state between 1999 and 2017. Major congenital anomalies were classified as affecting cerebral, cardiac, or other body systems, with further categorization as single or multisystem. We determined the potential for anomalies to contribute to the development of CP across causal pathway subgroups that were broadly categorized as developmental or involving destructive brain insults.Of persons with CP, 23% had major congenital anomalies and 17% of the cohort had anomalies that potentially contributed to the development of CP. Consistent with higher odds of parental consanguinity, maternal grand multiparity, and dysmorphic features in the group with anomalies, 82% of pathogenic anomalies, present in 14% of the cohort, were cerebral and involved developmental causal pathways. Only 3% (predominantly severe cardiac anomalies) were related to destructive brain insults.The study provides context for the impact on rates of CP of preventive measures or other changes in incidence or management of congenital anomalies. [ABSTRACT FROM AUTHOR]

Objective • The objective of this study was to investigate the clinical phenotype and genetic etiology of Glanzmann’s thrombasthenia in a consanguineous pedigree. Methods • Clinical data and ancillary test results were collected from pedigrees with Glanzmann’s thrombasthenia. High-throughput sequencing was used to detect variants in the proband. Candidate variants were verified by Sanger sequencing. Results • Two patients in the pedigree were homozygous for the c.2248C>T (p. Arg750Ter) variant of the ITGB3 gene. The parents and maternal grandmother, who didn’t have any recurrent haemorrhage, were found to carry a heterozygous c.2248C>T variant of the ITGB3 gene, which was absent in the aunt and paternal grandmother. Conclusion • The homozygous variant c.2248C>T (p. Arg750Ter) in the ITGB3 gene underlies the disease in this pedigree. This diagnosis will facilitate genetic counselling in this pedigree for better patient management and life guidance. [ABSTRACT FROM AUTHOR]

Atopic dermatitis often begins in infancy and follows a chronic course of exacerbations and remissions. The etiology is complex and involves numerous factors that contribute to skin barrier defect and inflammation. In the Middle East, the burden of atopic dermatitis is understudied. Epidemiological data specific to the Gulf region are scarce but reveal a prevalence of up to about 40% in the United Arab Emirates. Region-specific factors, such as the climate and the frequency of consanguineous marriages, may affect atopic dermatitis incidence, prevalence, and evolution over time. A panel of experts predominantly from the United Arab Emirates analyzed the evidence from published guidelines, and considered expert guidance and local treatment practices to develop clear recommendations for the management of atopic dermatitis in the United Arab Emirates. They encourage a systematic approach for the diagnosis and treatment, using disease severity scores and quality-of-life measurement tools. Treatment recommendations take into consideration both established therapies and the approved systemic biologics dupilumab and tralokinumab, and the Janus kinase inhibitors baricitinib, upadacitinib, and abrocitinib. [ABSTRACT FROM AUTHOR]

Background & Objectives: Ataxia is usually caused by cerebellar pathology or a decrease in vestibular or proprioceptive afferent input to the cerebellum. It is characterized by uncoordinated walking, truncal instability, body or head tremors, uncontrolled coordination of the hands, dysarthria, and aberrant eye movements. The objective of the current investigation was to identify the underlying genetic cause of the hereditary ataxia that affects the Pakistani population. Methods: We studied numerous consanguineous Pakistani families whose members had ataxia-related clinical symptoms to varying degrees. The families were chosen from the Punjab province, and the neurophysician conducted a clinical examination. Peripheral blood samples from both sick and healthy members of the family were taken after obtaining informed consent. Genomic DNA was used to find potential variations in probands using whole exome sequencing. The study was carried out at the University Hospital of Tübingen, Germany, and Government College University in Faisalabad, Pakistan, during 2018-2023. Results: The molecular analysis of these families identified different variants including SGCB: c.902C>T, c.668G>A, ATM: c.6196_6197insGAA, SPG11: c.5769del, SETX c.5525_5533del, and ATM: c.7969A>T. A noteworthy mutation in ATM and SETX was observed among them, and its symptoms were shown to cause ataxia in these families. Conclusion: The current study broadens the mutation spectrum of several hereditary ataxia types and suggests the next generation sequencing in conjunction with clinical research for a more accurate diagnosis of overlapping phenotypes of this disorder in the Pakistani population. [ABSTRACT FROM AUTHOR]

The incidence of rare diseases is expected to be comparatively higher in the Middle East and North Africa (MENA) region than in other parts of the world, attributed to the high prevalence of consanguinity. Most MENA countries share social and economic statuses, cultural relativism, religious beliefs, and healthcare policies. Polycystic kidney diseases (PKDs) are the most common genetic causes of kidney failure, accounting for nearly 8.0% of dialysis cases. The development of PKDs is linked to variants in several genes, including PKD1, PKD2, PKHD1, DZIP1L, and CYS1. Autosomal recessive PKD (ARPKD) is the less common yet aggressive form of PKD. ARPKD has an estimated incidence between 1:10,000 and 1:40,000. Most patients with ARPKD require kidney replacement therapy earlier than patients with autosomal dominant polycystic kidney disease (ADPKD), often in their early years of life. This review gathered data from published research studies and reviews of ARPKD, highlighting the epidemiology, phenotypic presentation, investigations, genetic analysis, outcomes, and management. Although limited data are available, the published literature suggests that the incidence of ARPKD may be higher in the MENA region due to consanguineous marriages. Patients with ARPKD from the MENA region usually present at a later disease stage and have a relatively short time to progress to kidney failure. Limited data are available regarding the management practice in the region, which warrants further investigations. [ABSTRACT FROM AUTHOR]

Congenital hypothyroidism (CH) is detected through a newborn screening program in Iran, enabling early detection and prompt treatment. This study addresses the longitudinal growth trajectory of Iranian children with CH and explores associated factors during the first 3 years of life. Data from 1474 children with CH in Isfahan, Iran (2002–2022), were analyzed. Weight, height, and head circumference were measured, and z-scores for age were calculated. Group-based trajectory modeling was applied to distinct growth trajectories. Factors influencing growth patterns, including gender, treatment initiation age, delivery method, parental consanguinity, history of familial hypothyroidism, and thyroid-stimulating hormone (TSH) levels at 3–7 days, were investigated. Thirty-seven percent of children diagnosed with CH faced a delay in weight, while 36.6% experienced stunted height, and 25.7% showed a retardation in head circumference growth. The initiation of treatment, parental consanguinity, and family history of hypothyroidism varied among these groups. Children exhibiting an optimal growth pattern in the initial 3 years of life demonstrated lower average TSH levels. Conclusion: This research emphasizes the complexity of managing CH and stresses the importance of tailoring interventions based on individualized characteristics and the ongoing growth patterns of the children. Future research is required to understand the intricate relationships between growth patterns and various determinants and optimize the growth and developmental outcomes of children with CH. What is Known: • Iran has a higher prevalence of congenital hypothyroidism (CH) with a nationwide screening program. • There are concerns about delayed growth in CH children, but limited research on long-term patterns and contributing factors. What is New: • Distinct patterns in weight, height, and head circumference among children with CH were identified. • Factors such as consanguinity, parental hypothyroidism, and TSH levels impact growth outcomes. • CH management is complicated, and there is a need for individualized interventions. [ABSTRACT FROM AUTHOR]

Introduction: Ataxia is one of the clinical findings of the movement disorder disease group. Although there are many underlying etiological reasons, genetic etiology has an increasing significance thanks to the recently developing technology. The aim of this study is to present the variants detected in WES analysis excluding non-genetic causes, in patients with ataxia. Methods: Thirty-six patients who were referred to us with findings of ataxia and diagnosed through WES or other molecular genetic analysis methods were included in our study. At the same time, information such as the onset time of the complaints, consanguinity status between parents, and the presence of relatives with similar symptoms were evaluated. If available, the patient's biochemical and radiological test results were presented. Results: Thirty-six patients were diagnosed through WES or CES. The rate of detected autosomal recessive inheritance disease was 80.5%, while that of autosomal dominant inheritance disease was 19.5%. Abnormal cerebellum was detected on brain MRI images in 26 patients, while polyneuropathy was detected on EMG in eleven of them. While the majority of the patients were compatible with similar cases reported in the literature, five patients had different/additional features (variants in MCM3AP, AGTPBP1, GDAP2, and SH3TC2 genes). Conclusions: The diagnosis of ataxia patients with unknown etiology is made possible thanks to these clues. Consideration of a genetic approach is recommended in patients with ataxia of unknown etiology. [ABSTRACT FROM AUTHOR]

AimsWerner Syndrome is a rare premature ageing autosomal recessive disorder caused by pathogenic variants in the WRN gene. People with Werner Syndrome may develop diabetes mellitus. Chronic foot ulceration is seen, with some characteristics overlapping with diabetic foot disease. However, the clinical course of the ulceration is atypical of diabetic foot disease. We present four siblings from an Irish Traveller family with Werner Syndrome to highlight the complexity of this condition. The Irish Traveller population are an indigenous, endogamous population in which consanguinity is common. As a result, rare autosomal recessive disorders are prevalent among this population:. Methods: We describe our experience managing the complex foot disease seen in all four siblings. Foot complications present in the siblings include painful peripheral neuropathy, chronic foor ulceration, underlying osteomyelitis and acral melanoma. Results: The cases are described individually, with a particular focus on the complex foot disease associated with the condition. Conclusions: Although the siblings attend a diabetic foot clinic, we suggest that the combination of clinical features seen in these cases is unique to Werner syndrome and warrants the title 'Werner Syndrome' (rather than 'Diabetic') foot. [ABSTRACT FROM AUTHOR]

Specific language impairment (SLI) is a developmental disorder with substantial genetic contributions. A genome-wide linkage analysis and homozygosity mapping were performed in five consanguineous families from Pakistan. The highest LOD scores of 2.49 at 12p11.22-q11.21 in family PKSLI-31 and 1.92 at 6p in family PKSLI-20 were observed. Homozygosity mapping showed a loss of heterozygosity on 1q25.3-q32.2 and 2q36.3-q37.3 in PKSLI-20. A loss of heterozygosity mapped, in PKSLI-31 and PKSLI-34 flanks, NFXL1 and CNTNAP2, which are genes previously identified in SLI. Our findings report novel SLI loci and corroborate previously reported SLI loci, indicating the utility of a family-based approach. [ABSTRACT FROM AUTHOR]

Abstract Background Preconception expanded carrier screening (ECS) is a genetic test that enables the identification of at-risk carriers of recessive disorders by screening for up to hundreds of genes. Next-generation sequencing (NGS) development has paved the way for its integration into ECS. This study aims to identify the carrier genetic status of couples experiencing or anticipating conception challenges through NGS-based ECS and to gain an overview of the rare genetic disorders in a population with increased consanguinity. Methods Thirty couples who presented to the Genetic Disease Clinic between 2015 and 2024 with failed reproductive outcomes or with a positive personal or family history of genetic disorders and underwent ECS were included and retrospectively analyzed. Results Fifty-four individuals (90.00%) were found to carry at least one variant of 95 identified genes, totaling 174 variants. Six individuals (10.00%) tested negative for any variant. Seven individuals had one variant (11.67%), 13 had two variants (21.67%), and 34 had 3 or more variants (56.67%). The most common variants identified were of HBA, HBB, CYP21A2, and G6PD genes. Most of the detected variants were unknown or unexpected (n = 143, 82.18%). Eight couples carried two or more variants in common. Consanguinity was reported in 14 couples (46.67%). Conclusions Preconception ECS is crucial for reproductive planning, permitting couples to evaluate their combined genetic risks and make informed decisions, reducing the chance of having children with genetic disorders.

Abstract Background Mucopolysaccharidosis type I is a lysosomal storage disease resulting from a deficiency in alpha-L-iduronidase (IDUA), which causes the accumulation of partially degraded dermatan sulfate and heparan sulfate. This retrospective study, spanning eight years, analyzed data from 45 MPSI patients. The report aimed to explore the potential origin of the p.P533R mutation in the Maghrebin population by constructing a single-nucleotide polymorphism haplotype around the IDUA gene, in order to propose a molecular proof of a founder effect of the MPSI/p.P533R allele. Patients and methods All of the studied patients were from Libya (2), Mauritania (1) Morocco (21) and Tunisia (21) with first cousins being the most frequent union. The diagnosis of MPSI patients often involves the combination of urinary screening, leukocyte IDUA activity determination, and DNA molecular analysis. In our study, to identify the common p.P533R mutation, we performed both DNA sequencing and tetra-primer ARMS PCR assay. Additionally, Haploview was used to determine the specific haplotype that cosegregates with the p.P533R mutation. Controls were genotyped to ensure that all the SNPs were in Hardy–Weinberg equilibrium. Results In the present report we confirmed the very strong impact of consanguinity on the incidence of MPSI disease. Furthermore, studied families of mixed ancestry shared common and specific haplotype, which was observed in studied populations, suggesting the presence of a founder effect in the North Africa. Conclusion The p.P533R missense mutation was identified in each patient originated from Libya, Mauritania, Morocco and Tunisia. Furthermore, these MPSI patients exhibited the same IDUA haplotype. The occurrence of a shared AAGGGTG haplotype, among North African populations may be attributed to substantial historical gene exchange between these groups, likely stemming from migration, inter-ethnic marriage, or other forms of interaction throughout history.

Lamia K Alshamlani,1 Dana S Alsulaim,1 Raghad S Alabbad,1 Ahad A Alhoshan,1 Joud F Alkhoder,1 Norah S Alsaleh,2 Mohammed Almannai,1– 3 Faroug Ababneh,2 Manal Algattan,4 Lojain Alsini,4 Abdulrahman Faiz Alswaid,2 Wafaa M Eyaid,1– 3 Fuad Al Mutairi,1– 3 Muhammad Umair,3 Majid Alfadhel1– 3 1College of Medicine, King Saud bin Abdulaziz University for Health Sciences (KSAU-HS), King Abdulaziz Medical City, Ministry of National Guard Health Affairs (MNG-HA), Riyadh, Saudi Arabia; 2Genetics and Precision Medicine Department (GPM), King Abdullah Specialized Children Hospital (KASCH), King Saud Bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, Ministry of National Guard Health Affairs (MNG-HA), Riyadh, Saudi Arabia; 3Medical Genomics Research Department, King Abdullah International Medical Research Center (KAIMRC), King Saud Bin Abdulaziz University for Health Sciences, Ministry of National Guard Health Affairs (MNGH), Riyadh, Saudi Arabia; 4Pathology and Laboratory Medicine Department, King Abdulaziz Medical City, Ministry of National Guard Health Affairs, Riyadh, Saudi ArabiaCorrespondence: Majid Alfadhel, Genetics and Precision Medicine Department (GPM), King Abdullah Specialized Children’s Hospital, King Abdulaziz Medical City, P.O Box 22490, Riyadh, 11426, Saudi Arabia, Tel +00 966 11 805 3560, Fax +00 966 11 805 5555, Email dralfadhelm@gmail.comBackground: Consanguinity, or the practice of marrying close relatives, is a common cultural tradition in Saudi Arabia, with rates among the highest in the world. This practice has significant implications for the prevalence and distribution of major single genetic defects and chromosomal abnormalities within the Saudi population.Methods: Herein, using the BESTCare electronic medical record system (designed to streamline hospital operations, enhance patient care, and improve the overall efficiency of healthcare services; bestcare.ezcaretech.com) in a single tertiary centre, King Abdullah Specialized Children Hospital (KASCH) in Riyadh, Saudi Arabia, we performed a cross-sectional study for all patients referred to the hospital from the 1st January 2020 until 1st January 2022.Results: The present study, which included 1100 individuals, found a high prevalence of consanguinity (64%) and a significant proportion of third-degree relatives (69%). The mean age of participants was 12.24 years, and the diagnostic rate using advanced molecular genetics techniques was 45%, with whole exome sequencing (WES) being the most common method (43%). The study also noted a significant delay in diagnosis for more than a year in 16% of cases, with a common neurodevelopmental phenotype (18%).Conclusion: In conclusion, we revealed the prevalence of consanguineous marriages in the KASCH hospital in Riyadh, Saudi Arabia. We also highlighted the most frequently referred phenotype. These findings are consistent with previous research on the prevalence and impact of consanguinity on rare genetic disorders.Keywords: consanguinity, genetic disorders, autosomal recessive disorders, Saudi Arabia, prevalence of single gene disorder, chromosomal abnormalities

Abstract We hypothesized that consanguineous marriage will remain a risk factor for pregnancy outcome and offspring mortality, but the development in demographic, socioeconomic conditions and increased utilization of maternal and child health care services during postglobalization era would work as a buffer in the reduction of child mortality rates. Data fromNational Family Health Surveys 4(2015–2016) and 5(2019–2021) were pooled and used for the analysis. Binary logistic regression and Cox proportional hazard regression models were used to examine the effects of close (CC) and distant (DC) consanguinity on spontaneous abortion, stillbirth, neonatal mortality, post-neonatal, and child mortality respectively compared to non-consanguinity (NC). The final model showed that the risk of spontaneous abortion (both CC and DC, p

Recessive alleles have been shown to directly affect both human Mendelian disease phenotypes and complex traits. Pedigree studies also suggest that consanguinity results in increased childhood mortality and adverse health phenotypes, presumably through penetrance of recessive mutations. Here, we test whether the accumulation of homozygous, recessive alleles decreases reproductive success in a human population. We address this question among the Namibian Himba, an endogamous agro-pastoralist population, who until very recently practiced natural fertility. Using a sample of 681 individuals, we show that Himba exhibit elevated levels of "inbreeding," calculated as the fraction of the genome in runs of homozygosity (FROH). Many individuals contain multiple long segments of ROH in their genomes, indicating that their parents had high kinship coefficients. However, we do not find evidence that this is explained by first-cousin consanguinity, despite a reported social preference for cross-cousin marriages. Rather, we show that elevated haplotype sharing in the Himba is due to a bottleneck, likely in the past 60 generations. We test whether increased recessive mutation load results in observed fitness consequences by assessing the effect of FROH on completed fertility in a cohort of postreproductive women (n = 69). We find that higher FROH is significantly associated with lower fertility. Our data suggest a multilocus genetic effect on fitness driven by the expression of deleterious recessive alleles, especially those in long ROH. However, these effects are not the result of consanguinity but rather elevated background identity by descent.

Individuals with inborn errors of immunity face challenges in fertility, pregnancy, and genetic disorder transmission. Prenatal genetic counseling is crucial, especially in tribal societies with consanguineous unions. Ten families with confirmed inborn errors of immunity were studied, revealing diverse pregnancy decisions: An architect with autosomal dominant STAT-1 gain of function underwent prenatal diagnosis despite initial plans for preimplantation genetic diagnosis. In a consanguineous family, two children died from leukocyte adhesion deficiency type 1 because the father refused prenatal diagnosis. First cousins opted against terminating the second pregnancy, resulting in two children affected by Bruton disease. Another consanguineous couple, with two children afflicted by ataxia-telangiectasia, chose oocyte donation for their third child, ensuring a healthy birth. Recurrent pregnancy loss was observed in a mother subsequently diagnosed with ZAP70 deficiency. A mother with Wiskott-Aldrich syndrome child opted for in vitro fertilization, leading to a healthy birth post-prenatal diagnosis. A misdiagnosis of anaplastic anemia occurred in a family with multiple instances of Wiskott-Aldrich syndrome. A leukocyte adhesion deficiency type 1 case led to parental dissolution due to the father's refusal to acknowledge the condition. In a non-consanguineous couple, the father's diagnosis of TACI deficiency influenced the mother's decision to discontinue pregnancy post-prenatal diagnosis. Genetic diagnosis alone cannot optimize prenatal care for immune dysregulation disorders. Various factors, including patient education, societal norms, ethics, and economics, impact pregnancy decisions. Clinical immunologists must integrate these elements into guidance strategies to enhance patient outcomes. [ABSTRACT FROM AUTHOR]

Background: Consanguineous marriage is a common practice in the Middle East and in Saudi Arabia especially. Not many studies were done on the relationship between consanguinity and congenital hearing loss (HL) in Saudi Arabia and none in the Eastern Region specifically. Therefore, this study focuses on the determination of the association between consanguinity and congenital HL (CHL). Materials and Methods: This is a comparative cross-sectional study that included any eastern region resident with severe-to-profound CHL. The data were collected and recorded on a structured questionnaire that was distributed among six schools in hard copy. In addition, data were also collected directly from two rehabilitation centers and from the Saudi Association for Hearing Impairment in Dammam. Results: Among 275 participants, the degree of HL was observed to be severe in 92 (33.5%) and profound in 183 (66.5%) participants. Consanguinity was reported to be as high as 75.6%. Most consanguineous marriages were of the first degree, which was found to have an association with higher numbers of severe and profound HL. It was observed that a total of 142 (51.7%) of the participants had at least one or more family members with HL, and 130 (47.3%) had at least one or more relatives with HL. Furthermore, it was found that those who reported blood-related parents had higher percentages of family members/relatives with the same condition. Conclusion: The outcome of this study is suggestive that there is an association between consanguineous marriage and having children with CHL. Looking at these findings and how consanguineous marriage is still commonly practiced, it is crucial to spread awareness regarding the dangers and possible associated disorders affecting children when marrying relatives.

Between the 8th and 11th centuries CE, the Iberian Peninsula underwent profound upheaval due to the Umayyad invasion against the Visigoths, resulting in population shifts and lasting demographic impacts. Our understanding of this period is hindered by limited written sources and few archaeogenetic studies. We analyzed 33 individuals from Las Gobas, a necropolis in northern Spain, spanning the 7th to 11th centuries. By combining archaeological and osteological data with kinship, metagenomics, and ancestry analyses, we investigate conflicts, health, and demography of these individuals. We reveal intricate family relationships and genetic continuity within a consanguineous population while also identifying several zoonoses indicative of close interactions with animals. Notably, one individual was infected with a variola virus phylogenetically clustering with the northern European variola complex between ~885 and 1000 CE. Last, we did not detect a significant increase of North African or Middle East ancestries over time since the Islamic conquest of Iberia, possibly because this community remained relatively isolated. [ABSTRACT FROM AUTHOR]

Attention deficit hyperactivity disorder (ADHD) is a clinically and genetically heterogeneous neurodevelopmental syndrome characterized by behavioral appearances such as impulsivity, inattention, and hyperactivity. The prevalence of ADHD is high in childhood when compared to adults. ADHD has been significantly advanced by genetic research over the past 25 years. However, it is logically conceivable that both genetic and/or non-genetic factors, such as postnatal environmental and social influences, are associated with ADHD phenotype in Arab populations. While genetic influences are strongly linked with the etiology of ADHD, it remains obscure how consanguinity which is an underlying factor for many genetic diseases, contributes to ADHD subtypes. Arabian Gulf Nations have one the highest rates of consanguineous marriages, and consanguinity plays an important contributing factor in many genetic diseases that exist in higher percentages in Arabian Gulf Nations. Therefore, the current review aims to shed light on the genetic variants associated with ADHD subtypes in Arabian Gulf nations and Saudi Arabia in particular. It also focuses on the symptoms and the diagnosis of ADHD before turning to the neuropsychological pathways and subgroups of ADHD. The impact of a consanguinity-based understanding of the ADHD subtype will help to understand the genetic variability of the Arabian Gulf population in comparison with the other parts of the world and will provide novel information to develop new avenues for future research in ADHD. [ABSTRACT FROM AUTHOR]

This research letter discusses the different phenotypes of ABL1 deficiency syndromes caused by mutations in different isoforms of the ABL1 gene. Somatic mutations in ABL1 are associated with cancer, while germline gain-of-function variants are linked to Congenital Heart Defects and Skeletal Malformations Syndrome (CHDSKM). Biallelic loss-of-function variants in ABL1 are associated with Human ABL1 Deficiency Syndrome (HADS). The letter presents a case study of a Lebanese family with a history of cardiac abnormalities, including a child with a stenotic subaortic membrane. The study highlights the various types of heart defects and genetic mutations in the ABL1 gene, suggesting that different mutations can lead to distinct phenotypes. Further research is needed to fully understand ABL1-associated disorders. The study was funded by the Lebanese American University and the authors have no conflicts of interest. [Extracted from the article]

ApoA-I amyloidosis is an extremely rare form of systemic amyloidosis that commonly involves the heart, kidneys, and liver. ApoA-I amyloidosis is caused by amyloidogenic variants of APOA1 that are inherited in an autosomal dominant manner. Here, we report a 69-year-old man with sporadic cardiac amyloidosis who was born to consanguineous parents and carried a homozygous variant of p.Leu202Arg in APOA1. [ABSTRACT FROM AUTHOR]

Background: Malaria can infect erythrocytes and hence cause different pathogenesis episodes leading to death mostly in pregnant women and children under the age of 5 years. The selective pressure of these parasites leads to the production of new human genetic diseases. The most prevalent genetic alterations in the human genome are thalassemia and hemoglobinopathies (Hb E, Hb S), which are recognized throughout the world, including Saudi Arabia. Methods: From May 2018 to August 2019, 13972 Saudi citizens from King Fahd Central Hospital and premarital facilities in the Saudi Arabian province of Jazan participated in this study. This study aims to compare the prevalence of Hb E and other hemoglobinopathies in positive versus negative cases of malaria. So, CBC, malaria test, Hb-electrophoresis, and molecular study were investigated. Result: For thalassemias and Hb disorders, 36% with abnormal Hb (47% of them) carried Hb S in their blood, 37% with α-thalassemia, 11% for β-thalassemia and 4% of Hb E. Significant variations in CBC parameters were observed in Hb E patients. There was significant decrease in MCV, MCH and MCHC and slightly increase in WBCs, RBCs, RDW and PLT as compared to controls. [ABSTRACT FROM AUTHOR]

Leber congenital amaurosis (LCA) and early‐onset retinal degeneration (EORD) are inherited retinal diseases (IRD) characterized by early‐onset vision impairment. Herein, we studied 15 Saudi families by whole exome sequencing (WES) and run‐of‐homozygosity (ROH) detection via AutoMap in 12/15 consanguineous families. This revealed (likely) pathogenic variants in 11/15 families (73%). A potential founder variant was found in RPGRIP1. Homozygous pathogenic variants were identified in known IRD genes (ATF6, CRB1, CABP4, RDH12, RIMS2, RPGRIP1, SPATA7). We established genotype‐driven clinical reclassifications for ATF6, CABP4, and RIMS2. Specifically, we observed isolated IRD in the individual with the novel RIMS2 variant, and we found a retina‐enriched RIMS2 isoform conserved but not annotated in mouse. The latter illustrates potential different phenotypic consequences of pathogenic variants depending on the particular tissue/cell‐type specific isoforms they affect. Lastly, a compound heterozygous genotype in GUCY2D in one non‐consanguineous family was demonstrated, and homozygous variants in novel candidate genes ATG2B and RUFY3 were found in the two remaining consanguineous families. Reporting these genes will allow to validate them in other IRD cohorts. Finally, the missing heritability of the two unsolved IRD cases may be attributed to variants in non‐coding regions or structural variants that remained undetected, warranting future WGS studies. [ABSTRACT FROM AUTHOR]

A 22-month-old girl of consanguineous parents was admitted with a high-grade fever. She was found to have insensitivity to painful stimuli and an absence of perspiration. She also displayed self-mutilating behaviour and was insensitive to cold/hot water on her body. On examination, there was loss of the tip of the tongue, missing teeth, generalised xerosis, and several ulcers at sites of minor trauma. She also had dysplastic nails and digital ulcers. Sensory examination demonstrated a complete lack of awareness of pain and temperature, vibration and fine touch were intact and lacrimation was normal. Differential diagnoses of hereditary sensory and autonomic neuropathy (HSAN), Lesch—Nyhan syndrome, hypohidrotic ectodermal dysplasia and leprosy were considered. Results of routine blood investigations including serum uric acid were normal. On performing clinical exome sequencing, the diagnosis of congenital insensitivity to pain with anhidrosis (CIPA) of autosomal recessive inheritance was confirmed. A novel, predicted to be pathogenic variant detected at exon 16 of the NTRK1 gene resulting in congenital insensitivity to pain with anhidrosis is reported. Abbreviations: CIPA: congenital Insensitivity to pain with anhidrosis; HSAN: hereditary sensory and autonomic neuropathy; NGF: nerve growth factor; NTRK1: neurotrophic tyrosine kinase receptor 1 gene; TrKA: tropomyosin receptor kinase A. [ABSTRACT FROM AUTHOR]

The conservation of animal genetic resources refers to measures taken to prevent the loss of genetic diversity in livestock populations, including the protection of breeds from extinction. Creole cattle populations have suffered a drastic reduction in recent decades owing to absorbent crosses or replacement with commercial breeds of European or Indian origin. Genetic characterization can serve as a source of information for conservation strategies to maintain genetic variation. The objective of this work was to evaluate the levels of inbreeding and kinship through the use of genomic information. A total of 903 DNAs from 13 cattle populations from Argentina, Bolivia and Uruguay were genotyped using an SNP panel of 48 K. Also, a dataset of 76 K SNPs from Peruvian Creole was included. Two inbreeding indices (FROH and Fhat2) and kinship relationships were calculated. In addition, effective population size (Ne), linkage disequilibrium, population composition and phylogenetic relationships were estimated. In Creole cattle, FROH ranged from 0.14 to 0.03, and Fhat2 was close to zero. The inferred Ne trends exhibited a decline toward the present for all populations, whereas Creole cattle presented a lower magnitude of Ne than foreign breeds. Cluster analysis clearly differentiated the taurine and Zebu components (K2) and showed that Bolivian Creole cattle presented Zebu gene introgression. Despite the population reduction, Creole populations did not present extreme values of consanguinity and kinship and maintain high levels of genetic diversity. The information obtained in this work may be useful for planning conservation programmes for these valuable local animal genetic resources. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to screen the genetic etiology for the high-risk families including those with an adverse pregnancy history, a history of consanguineous marriages, or a history of genetic diseases, but lack of proband via whole exome sequencing (WES). Methods: 128 individuals from high-risk family were tested by WES. The candidate variants were analyzed according to the ACMG criteria to screen the potential carriers. At-risk couples (ARCs) who harbored the same causative gene were provided with precise fertility guidance to avoid the birth of children with birth defects. Results: The total detection rate was 36.72%, with pathogenic/likely pathogenic (P/LP) variants found in 47 individuals, and variants of uncertain significance (VUS) were found in 34. Among couples with adverse pregnancy history: P/LP variants were found in 38 individuals, and VUS were found in 26, for a detection rate of 34.55%; among members of family history of genetic disease or consanguineous marriages: P/LP variants were found in nine individuals, and VUS were found in 8, for a detection rate of 50.00%. Otherwise, we detected 19 ARCs who both carried P/LP variants in the same gene, with a theoretical offspring prevalence of up to 7.42%. Conclusion: In the absence of probands, carrier screening using WES can provide an efficient tool for screening the molecular etiology of high-risk families. [ABSTRACT FROM AUTHOR]

Genetic diversity can be seen as a source of options to grow diverse and nutritious foods with fewer resources, adapted to more hostile environments and making crops less susceptible to pests. In this sense, the present work was carried out with the objective of determining the genetic diversity, based on their genealogy, of the 20 rice cultivars released by the National Institute of Agricultural Sciences of Cuba in the 1984-2020 period. Through the CROPDIVER V. 01.20.19 program, the combined genealogical tree of all cultivars was elaborated, their parentage coefficients, the percentage of participation and the contribution of each ancestor in the cultivars obtained were calculated, in addition the dendrogram was constructed using parentage coefficient as genetic similarity estimate. The results showed that the genealogical tree, of the 20 cultivars obtained, is made up of 28 Ancestors and 65 cultivars or improved lines, the highest level of contribution falls on four ancestors and 12 contribute the genes present in the cytoplasm, through the maternal way. Although, as a whole, the obtained germplasm is consanguineous, the grouping carried out differentiated three groups of cultivars that allow establishing genetic similarities between them and making recommendations for their use in Cuban rice production. [ABSTRACT FROM AUTHOR]

Worldwide, more than 130 million infants are born each year and a considerable number of 13.5 million of these children have inbred parents. The present study aimed to investigate the association between parents' consanguinity and chronic illness among their children and grandchildren in India. The nationally representative data, Longitudinal Aging Study in India, 2017–2018, Wave 1 was used for the present study. Bivariate analysis, a probit model, and propensity score estimation were employed to conduct the study. The study observed the highest prevalence of consanguinity marriage in the state of Andhra Pradesh (28%) and the lowest in Kerala (5%) among the south Indian States. People who lived in rural areas, belonged to the richer wealth quintile and Hindu religion were the significant predictors of consanguinity marriage in India. For individuals who were in consanguineous marriages, there was 0.85%, 0.84%, 1.57% 0.43%, 0.34%, and 0.14% chances of their children and grandchildren developing psychotic disorders, heart disease, hypertension stroke, cancer, and diabetes, respectively. Moreover, around 4.55% of the individuals have a history of birth defects or congenital disorders. To address the risk of complicated illnesses due to the consanguinity of marriage, medical, genetic, and social counselling services are required. [ABSTRACT FROM AUTHOR]

Exome sequencing (ES) has been utilized in diagnosing children with neurodevelopmental manifestations, this study aimed to investigate the utility of ES in children within a highly consanguineous population that presented with neurodevelopmental complaints. A retrospective chart review was performed for 405 children with neurodevelopmental complaints who have had ES and were evaluated in multiple centers in the United Arab Emirates over a four‐year period. Within the cohort of 405 children, consanguinity was reported in 35% (144/405). The primary clinical presentations were developmental delay/cognitive impairment, distinctive facial features, hypotonia, seizures, and weakness. The diagnostic yield was 57% (231/405). Novel variants were identified in 54% (125/231) of positive cases. Within the positive cases, specific treatment was available in 6% (13/231) and copy number variants (CNV) were reported in 3% (8/231) of cases. In eight children, variants in genes that have not yet been linked to human disease that could potentially be the cause of the observed phenotype "candidate genes" were identified. ES was utilized effectively within this cohort with a high diagnostic yield and through the identification of novel gene variants, CNVs, candidate genes and secondary findings as well as the alteration of the treatment plan in cases where treatment was available. [ABSTRACT FROM AUTHOR]

Epigenetics in the form of DNA methylation and other processes is an established property of genotypes and a focus of empirical research. Yet, there remain fundamental gaps in the evolutionary theory of epigenetics. To support a comprehensive understanding of epigenetics, this paper investigates theoretically the combined effects of deleterious mutation and epimutation with and without inbreeding. Both spontaneous epimutation and paramutation are considered to cover a broader range of epigenetic phenomena. We find that inbreeding generally reduces the amount of segregating deleterious genetic and epigenetic variation at equilibrium, although interestingly inbreeding can also increase the amount of deleterious genetic or epigenetic variation. Furthermore, we also demonstrate that epimutation indirectly can cause increased or decreased deleterious genetic variation at equilibrium relative to classic expectations, which is particularly evident when paramutation is occurring. With the addition of deleterious epimutation, there may be significantly increased purging of deleterious variation in more inbred populations and a significantly increased amount of segregating deleterious variation in more outbred populations, with notable exceptions. [ABSTRACT FROM AUTHOR]

Patients with very early-onset inflammatory bowel disease (VEO-IBD) may present because of underlying monogenic inborn errors of immunity (IEI). Strong differences have been observed in the causes of monogenic IBD among ethnic populations. This multicenter study was carried out on 16 Iranian patients with VEO-IBD. We reviewed clinical and basic immunologic evaluation including flow cytometry and immunoglobulin levels. All patients underwent clinical whole exome sequencing (WES). Sixteen patients (8 females and 8 males) with a median age of 43.5 months were enrolled. The median age at the onset of symptoms was 4 months. Most patients (12, 75%) had consanguineous parents. Chronic non-bloody diarrhea (13, 81.3%) and perianal diseases including perianal abscess (6, 37.5%), anal fissure (6, 37.5%), or anal fistula (2, 12.5%) were the most common manifestations. WES identified a spectrum of genetic variants in 13 patients (81.3%): IL10RB (6, 37.5%), MVK (3, 18.8%), and CASP8, SLC35C1, G6PC3, and IKBKB in 1 patient, respectively. In 3 patients (18.7%), no variant was identified. Flow cytometry identified a spectrum of abnormalities that helped to assess the evidence of genetic diagnosis. At the end of the survey, 3 (18.8%) patients were deceased. This high rate of monogenic defects with a broad spectrum of genes reiterates the importance of investigating IEI in patients with infantile-onset IBD. Patients with very early-onset inflammatory bowel disease (VEO-IBD) may present because of underlying monogenic inborn errors of immunity (IEI). Strong differences have been observed in the causes of monogenic IBD among ethnic populations. The high rate of monogenic defects with a broad spectrum of genes reiterates the importance of investigating IEI in patients with infantile-onset IBD. Graphical Abstract [ABSTRACT FROM AUTHOR]

Background: Von Willebrand disease (VWD) is one of the most common coagulative diseases, so identifying the effective factors in preventing this complication is essential. The aim of this study is to evaluate the frequency of demographic and epidemiological findings in VWD patients referred to a hospital in Zahedan, Iran. Materials and Methods: This study was performed on 76 patients with VWD referred to Hazrat Ali-Asghar Hospital in Zahedan city, Sistan, and Baluchestan province. After obtaining consent from the patients, the demographic information and clinical symptoms of the disease were recorded. All statistical analyses were performed using SPSS 22.0 software. All descriptive data were expressed as mean ±SD and percent (%) depending on the continuous and dichotomous variables. A P-value ≤0.05 was considered significant statistically. Results: The present study results showed that the highest age group of VWD patients at the time of disease diagnosis was in the age group 1-5 years (47.3%), and most patients had type III VWD (80.3%). It was also found that 67.1% of patients had a positive family history and their parents' consanguineous marriage (77.6%). The most common complaints were epistaxis (88.15%), cutaneous bleeding (78.94%), and oral cavity bleeding (61.84%), respectively. Conclusion: Due to the high prevalence of VWD in consanguineous marriages and an increase in adverse complications and symptoms in VWD patients, the proper diagnosis and screening at an early age, especially in people with family history, is essential. Efforts are needed to develop national registries and widely provide the required and available basic services for diagnosis and treatment. [ABSTRACT FROM AUTHOR]

Runs of homozygosity (ROHs) are indicative of elevated homozygosity and inbreeding due to mating of closely related individuals. Self-fertilization can be a major source of inbreeding which elevates genome-wide homozygosity and thus should also create long ROHs. While ROHs are frequently used to understand inbreeding in the context of conservation and selective breeding, as well as for consanguinity of populations and their demographic history, it remains unclear how ROH characteristics are altered by selfing and if this confounds expected signatures of inbreeding due to demographic change. Using simulations, we study the impact of the mode of reproduction and demographic history on ROHs. We apply random forests to identify unique characteristics of ROHs, indicative of different sources of inbreeding. We pinpoint distinct features of ROHs that can be used to better characterize the type of inbreeding the population was subjected to and to predict outcrossing rates and complex demographic histories. Using additional simulations and four empirical datasets, two from highly selfing species and two from mixed-maters, we predict the selfing rate and validate our estimations. We find that self-fertilization rates are successfully identified even with complex demography. Population genetic summary statistics improve algorithm accuracy particularly in the presence of additional inbreeding, e.g. from population bottlenecks. Our findings highlight the importance of ROHs in disentangling confounding factors related to various sources of inbreeding and demonstrate situations where such sources cannot be differentiated. Additionally, our random forest models provide a novel tool to the community for inferring selfing rates using genomic data. [ABSTRACT FROM AUTHOR]

Inherited retinal diseases (IRDs) are extremely heterogeneous with at least 350 causative genes, complicating the process of genetic diagnosis. We analyzed samples of 252 index cases with IRDs using the Blueprint Genetics panel for "Retinal Dystrophy" that includes 351 genes. The cause of disease could be identified in 55% of cases. A clear difference was obtained between newly recruited cases (74% solved) and cases that were previously analyzed by panels or whole exome sequencing (26% solved). As for the mode of inheritance, 75% of solved cases were autosomal recessive (AR), 10% were X-linked, 8% were autosomal dominant, and 7% were mitochondrial. Interestingly, in 12% of solved cases, structural variants (SVs) were identified as the cause of disease. The most commonly identified genes were ABCA4, EYS and USH2A, and the most common mutations were MAK-c.1297_1298ins353 and FAM161A-c.1355_1356del. In line with our previous IRD carrier analysis, we identified heterozygous AR mutations that were not the cause of disease in 36% of cases. The studied IRD panel was found to be efficient in gene identification. Some variants were misinterpreted by the pipeline, and therefore, multiple analysis tools are recommended to obtain a more accurate annotation of potential disease-causing variants. [ABSTRACT FROM AUTHOR]

The family, which is one of the oldest and most established institutions in human history, has not always just been a reasonable arrangement for achieving biological continuance as well as sexual, emotional, and material support, it has also been one of the basic components for the creation of civilization, culture, and society. There are various types of families, one of which is the endogamous family formed by the custom of consanguineous marriage within a very defined and distinct group. Our article concentrates on the question of how modernity and prosperity have influenced endogamy in modern Iran and whether this will change historical patterns and traditions or, perhaps, only broaden them within Iran's newly developed and modern society. Our conclusion is that, in Iran's uncertain environment, tradition may actually be strengthened. [ABSTRACT FROM AUTHOR]