Consanguineous Marriage Research Articles

Genetic insights into congenital hypothyroidism in three Iranian Azeri families with consanguineous marriage: the role of novel and recurrent TPO gene variations

This study aims to examine TPO gene mutations in congenital hypothyroidism (CH) within consanguineous Iranian Azeri families. Three families were subjected to next-generation sequencing and were subsequently validated using Sanger sequencing. The investigation revealed three homozygous pathogenic variants, one of which was identified as a novel variation, occurring within the TPO gene. These findings emphasize the notable prevalence of TPO gene mutations in Iranian Azeri affected by CH, thus establishing the pathogenic nature of the newly discovered variation in the studied patients.

Genetic heterogeneity in autosomal recessive hearing loss: a survey of Brazilian families

IntroductionHearing loss is a frequent sensory impairment type in humans, with about 50% of prelingual cases being attributed to genetic factors. Autosomal recessive hearing loss (ARHL) exhibits great locus heterogeneity and is responsible for 70%–80% of hereditary nonsyndromic cases.MethodsA total of 90 unrelated Brazilian individuals were selected for having hearing loss of presumably autosomal recessive inheritance, either born from consanguineous marriages or belonging to families with two or more affected individuals in the sibship and most cases were of normal hearing parents. In all cases, common pathogenic variants in GJB2 (c.35delG), GJB6 [del(GJB6-D13S1830) and del(GJB6-D13S1854)] and MT-RNR1 (m.1555A>G) were discarded and most were previously assessed by complete Sanger sequencing of GJB2. Their genetic material was analyzed through next-generation sequencing, targeting 99 hearing loss-related genes and/or whole exome sequencing.ResultsIn 32 of the 90 probands (36,7%) causative variants were identified, with autosomal recessive inheritance confirmed in all, except for two cases due to dominant variants (SIX1 and P2RX2). Thirty-nine different causative variants were found in 24 different known hearing loss-associated genes, among which 10 variants are novel, indicating wide genetic heterogeneity in the sample, after exclusion of common pathogenic variants. Despite the genetic heterogeneity, some genes showed greater contribution: GJB2, CDH23, MYO15A, OTOF, and USH2A.ConclusionThe present results confirmed that next-generation sequencing is an effective tool for identifying causative variants in autosomal recessive hearing loss. To our knowledge, this is the first report of next-generation sequencing being applied to a large cohort of pedigrees with presumable autosomal recessive hearing loss in Brazil and South America.

Case Report on Griscelli Syndrome with Hemophagocytic Lymphohistiocytosis

Objective: This case report was written with the intention of educating pediatric caregivers regarding the early detection and management of Griscelli Syndrome type 2 (GS2), thereby preventing fatal consequences, and to draw light on the necessity for premarital genetic counselling and education in public. Case Report: A two months and 7 days old male baby presented with tachycardia, fever, abdominal distension, cough, loose stools, and vomiting. Head to toe examination showed hypo-pigmented hair with silvery grey eyebrows and eyelashes. Bone marrow aspiration showed increased histiocytes exhibiting haemophagocytosis. Suspecting Griscelli Syndrome, genetic test was done which indicated RAB27A gene mutations, thereby confirming the GS2 diagnosis. The child was treated with 2 litres of oxygen with nasal prong, meropenem, fluconazole, dexamethasone and packed red blood cell transfusion. In view of worsening sepsis baby was given with vancomycin, tigecycline and cyclosporine and later intubated. Conclusion: Consanguineous marriages are common in India and are one of the major reason for autosomal recessive disorders like GS2 in newborns. This highlights the need of both premarital genetic counseling and education among public. Keywords: Hypopigmented hair, haemophagocytosis, abdominal distension, RAB27A mutation

Independent Occurrence of Two Cases of Lennox — Gastaut Syndrome and Neurofibromatosis in the Family: A Clinical Observation

Developmental and epileptic encephalopathies (DEE) are the most difficult problem in epileptology. Lennox — Gastaut syndrome (LGS) is a developmental and epileptic encephalopathy with onset in childhood, manifested by: frequent polymorphic seizures, including tonic axial ones; severe cognitive impairment; slow activity (with a frequency of <2.5–3.0 Hz) sharp-slow wave in the interictal period on the electroencephalogram, as well as runs of fast activity with a frequency of 10–20 Hz, often associated with tonic seizures; and resistance to therapy. Presumably genetic or forms with an unknown cause account for 20–30 % of cases of LGS, but a family history of epilepsy among patients with LGS is observed in only 2.5 %.The purpose of this work was to describe a familial case of LGS in two siblings.Materials and methods. A retrospective description of the medical history of 3 siblings born in a consanguineous marriage was performed.Results and discussion. There was a similarity in the course of the disease in the two brothers, absolute resistance to drug antiepileptic therapy and temporary effectiveness of hormonal therapy for LGS with a decrease in the duration of the effect from course to course. In addition, the rare parallel existence in this family of another autosomal dominant disease — neurofibromatosis type 1 — is shown.Conclusion. A detailed description of LGS within one family will not only expand doctors’ knowledge of this disease and the difficulties of its treatment, but also improve understanding of the genetic mechanisms of the development of DEE.

Atulyagotreeya Vivaha: A scientific review and case series on non-consanguineous marriage

Atulya Gotra Vivaha (non-consanguineous marriages), emphasized in Ayurveda and supported by modern genetics, plays a crucial role in reducing the risk of congenital anomalies and genetic disorders. Ancient Ayurvedic texts, such as Acharya Charaka’s Atulyagotreeya Sharira Adhyaya, advocate marrying outside one's Gotra to prevent the inheritance of faulty genes and ensure healthier progeny. Modern science also confirms that consanguineous marriages increase the risk of autosomal recessive disorders like mental retardation and congenital anomalies. Despite these insights, cultural norms, ignorance, and lack of awareness drive individuals, especially in less-educated communities, to practice consanguineous marriages, risking the life and health of future generations. This review highlights the need for awareness and education regarding the risks of such unions. Promoting Atulya Gotra marriages can help reduce the burden of genetic disorders and protect every child's life, which is invaluable to the well-being of society.

Illegal Marriages

Pope Innocent III has drawn constant scholarly attention in the realm of medieval history. Not only was his papacy fundamental in the shaping of the modern-day Roman Catholic Church, but his time as Roman Pontiff is also considered the apogee of the medieval papacy. He expanded papal influence into realms previously dreamt of by Church reformers and exerted it over secular rulers. An often-contested topic of Innocent’s historiography is the motivations and justifications for his actions. Are we to view them through the lens of reform or the mind of a pragmatist? This paper contributes to this debate by analyzing Innocent’s letters and actions pertaining to the consanguineous marriages of Alfonso IX with Berenguela in the Iberian Peninsula and Otto IV with Beatrix in the German lands. By comparing the actions and justifications of Pope Innocent III in the Iberian Peninsula and the German lands—an area on the periphery of Europe and one central in it—this paper seeks to uncover, firstly, whether Innocent acted similarly in comparable situations from both areas and, secondly, whether Church reform or pragmatism influenced his arguments and measures. This paper finds that Innocent acted in a reformist manner (disregarding temporal outcomes in favor of spiritual strictness) in the Iberian Peninsula while he focused on temporal matters through a pragmatic approach in the German lands due to the severe threat the German Empire posed to Church independence and the ongoing Reconquista in Iberia. Utilizing a comparatist approach to this topic allows for conclusions to be made from his actions in different regions rather than a case study in a singular region.

Exome Sequencing of Consanguineous Pashtun Families With Familial Epilepsy Reveals Causative and Candidate Variants in TSEN54, MOCS2, and OPHN1.

Next-generation sequencing is advancing in low- and middle-income countries, but accessibility remains limited. In Pakistan, many members of the Pashtun population practice familial marriage and maintain distinct socio-cultural traditions, isolating them from other ethnic groups. As a result, they may harbor genetic variants that could unveil new gene-disease associations. To investigate the genetic basis of epilepsy in the Pashtun community we recently established a collaboration between Bannu University and the University of Tuebingen. Here we report our first results of exome sequencing of four families with presumed monogenetic epilepsy and Mendelian inheritance pattern. In Family #201, we identified distinct disease-causing variants. One had a homozygous pathogenic missense variant in TSEN54 (c.919G > T, p.(Ala307Ser)), linked to Pontocerebellar Hypoplasia Type 2A. The second individual had a homozygous class IV missense variant in MOCS2 (c.226G > A, p.(Gly76Arg)) which is associated with Molybdenum cofactor deficiency. In family EP02, one affected individual carried a heterozygous class III variant in OPHN1 (c.1490G > A, p.(Arg497Gln)), related to syndromic X-linked intellectual disability with epilepsy. Our small study demonstrates the promise of next-generation sequencing in genetic epilepsies among the Pashtun population. Diagnostic next-generation sequencing should be established in Pakistan as soon as possible, and if not feasible, genetic research projects may pioneer this path.

Spinal muscular atrophy carrier screening program: awareness and attitude of healthcare professionals in Turkey.

Spinal Muscular Atrophy (SMA) is an autosomal recessive disease caused by variants in the SMN1 gene, leading to progressive muscle weakness. The carrier frequency of SMN1 gene variants, including variant and copy number variations, is estimated to be around 1 in 50 people, while the global prevalence of SMA is 1-3 per 10,000 live births. In response to the increasing carrier proportion, especially due to consanguineous marriages, Turkey launched the SMA Carrier Screening Program in 2021. Notably, recent SMA cases have been observed in the children of healthcare workers who did not undergo carrier screening, prompting us to evaluate their awareness of this program. After receiving ethics approval, 1,322 healthcare professionals completed a 15-item survey based on the SMA Carrier Screening Guidelines. Of these, 5.8% were unaware of SMA, and 26% lacked information about the national screening program. Awareness of the screening program was significantly lower among secondary and tertiary healthcare professionals compared to primary healthcare professionals (p < 0.0001) and among non-physician healthcare professionals compared to physicians (p < 0.0001). Additionally, a serious lack of knowledge was observed concerning the parts of the screening covering the pregnancy period. Although there is generally high awareness of the SMA Carrier Screening Program among healthcare professionals, significant knowledge gaps exist. These findings highlight the need for increased efforts to more effectively deliver screening programs and continue the education of healthcare professionals. Education and awareness campaigns can enhance program awareness and effectiveness, reach wider audiences, and contribute to preventive measures for the health of future generations.

Fanconi anemia diagnosed by genetic testing

Background : Fanconi anemia (FA) is a rare genetic disorder inherited in an autosomal recessive manner. The clinical phenotype varies depending on the involvement of different genes. Major physical abnormalities mainly affect the limbs and spine.. Methods/Observation : We report the case of an 11-year-old girl from a first-degree consanguineous marriage. The classic triad of short stature, malformation syndrome and early bone marrow failure suggested AF, which was confirmed by the detection of significant chromosomal instability after culture with Mitomycin C, compared with a normal control. Conclusion : This case highlights the crucial role of cytogenetics in the diagnosis of Fanconi anemia and genetic counseling to improve the management of affected children and their families. Keywords : Fanconi anemia; chromosomal breaks; mitomycin C.

Exploring the Balance: Cultural and Medical Perspectives on Cousin Marriages in Scheduled Castes and Other Communities

Exploring the Balance: Cultural and Medical Perspectives on Cousin Marriages in Scheduled Castes and Other Communities

Emphasizing the need for preconceptional, prenatal genetic counseling and comprehensive genetic testing in consanguinity: challenges and experience.

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.

Alopecia patterns and trichoscopic findings in patients with autosomal recessive congenital ichthyosis.

Autosomal recessive congenital ichthyosis (ARCI) is a rare genodermatosis categorized among nonsyndromic ichthyoses. While ARCI patients often manifest hair abnormalities, their impact on the quality of life remains underreported in the literature. This study aims to comprehensively characterize the clinical and trichoscopic findings of alopecia in ARCI patients. A prospective study spanning from January 2019 to December 2021 (3 years) was conducted at the Dermatology Department of Habib Thameur Hospital, Tunis, Tunisia. Clinical and trichoscopic examinations were performed on the hair of the participants, with molecular studies conducted on 15 patients. The study included 30 patients, predominantly female (male/female = 0.58), with a mean age of 20 years. Twenty-eight patients were born from consanguineous marriages. Lamellar ichthyosis was observed in 22 cases, while congenital ichthyosiform erythroderma and bathing suit ichthyosis were each present in 4 cases. The ARCI severity score, assessed using the Visual Index For Ichthyosis Severity scale, had a mean value of 15 (4-28). Alopecia emerged as a prominent finding in 11 patients, presenting as hairline recession (13%), multiple patchy alopecia (27%), and alopecia of the eyebrows (13%). Trichoscopic findings included interfollicular and perifollicular scaling, perifollicular lamellar hyperkeratosis, peripilar casts, interfollicular erythema, loss of hair openings, predominance of single hair follicles, broken hair, vellus hair, anisotrichosis, pili torti, dystrophic hair, and comma hair. Several trichoscopic findings showed statistically significant associations with the severity of ARCI. In our study, we only included 30 patients due to the rarity of this genodermatosis. Contrary to previous perceptions, alopecia is a notable finding in ARCI, particularly in patients with a severe form. This study provides a detailed characterization of alopecia in ARCI, shedding light on its prevalence and associated trichoscopic features, thereby enhancing our understanding of this dermatological condition.

Genetic testing perspectives in Pakistani population: a survey on knowledge, attitudes, awareness, and concerns.

A higher rate of consanguineous marriages is associated with the increasing prevalence of genetic disorders, imposing a significant burden on families, public health, and healthcare systems. Genetic testing facilitates the earlier detection of disease and personalized treatment approaches. Therefore, this study aims to assess knowledge, awareness, attitudes, and concerns regarding genetic testing in the Pakistani population. Participants (n = 494) were asked about factors that influence attitudes toward undergoing genetic testing. Furthermore, the study also investigates the concerns and reservations held by the Pakistani population regarding genetic testing. Participants indicated that consanguineous marriages lead to an increased risk of hereditary disorders and agreed that knowledge of genetic diseases can improve the quality of life. Almost 80% of the respondents know the term, and the majority of them know about genetic testing. 87.7% of respondents agreed to genetic screening before marriage, and 39.9% were willing to undergo genetic testing. More knowledge was significantly associated with a higher likelihood of accepting genetic testing, indicating potential acceptance if integrated into standard procedures. Those with a family history of genetic disorders were more positive in accepting genetic testing. The level of understanding regarding genetic testing also influences the concerns. Cultural or religious beliefs may also affect the decision to accept genetic testing. The survey reveals diverse opinions and knowledge levels regarding genetic testing in Pakistan. While there was generally positive interest, concerns about privacy, accuracy, and cultural factors should be addressed. Education and awareness campaigns could help improve understanding and acceptance.

Genetic variant profiling of neonatal diabetes mellitus in Iranian patients: Unveiling 58 distinct variants in 14 genes.

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. 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. 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. 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.

Tremor Ataxia With Central Hypomyelation Phenotype Related to a Recurrent POLR3A Mutation in Six Unrelated Tunisian Families.

POLIII-related leukodystrophies are a group of recently recognized hereditary white matter diseases with a similar clinical and radiological phenotype. No Tunisian studies have been published about POLIII-related leukodystrophy due to POLR3A variants. The aim of this study was to contribute to the clinical, radiological, and genetic characterization of POLR3A-related leukodystrophy in a Tunisian cohort. We report six cases of genetically confirmed POLR3A-related leukodystrophy belonging to six unrelated Tunisian families, along with a review of previously published pediatric cases. All patients were born to consanguineous marriages and originated from the North or the Center of Tunisia. Age at onset varied between 15 months and 6 years. The clinical phenotype was similar in all patients with cerebellar ataxia, tremor, and nystagmus being the key features. Brain imaging showed diffuse hypomyelination in all patients with progressive cerebellar atrophy in three patients. Molecular analysis identified the same bi-allelic NM_007055.4:c.2011T>C; p.(Trp671Arg) variant in the POLR3A gene in all patients. We hypothesize a founder effect for the identified variant given its recurrence in six unrelated individuals with a similar clinical phenotype. Given the apparent genetic homogeneity of Tunisian POLR3A patients, the recurrent variant should be directly targeted. This should facilitate diagnosis in index patients, and genetic counseling.

Consanguinity and Occurrence of Monogenic Diseases in a Single Tertiary Centre in Riyadh, Saudi Arabia: A 2 Years Cross-Sectional Study.

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. 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. 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%). 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.

Rare homozygous cilia gene variants identified in consanguineous congenital heart disease patients.

Congenital heart defects (CHD) appear in almost one percent of live births. Asian countries have the highest birth prevalence of CHD in the world. Recessive genotypes may represent a CHD risk factor in Asian populations with a high degree of consanguineous marriages. Genetic analysis of consanguineous families may represent a relatively unexplored source for investigating CHD etiology. To obtain insight into the contribution of recessive genotypes in CHD we analysed a cohort of forty-nine Pakistani CHD probands, originating from consanguineous unions. The majority (82%) of patient's malformations were septal defects. We identified protein altering, rare homozygous variants (RHVs) in the patient's coding genome by whole exome sequencing. The patients had a median of seven damaging RHVs each, and our analysis revealed a total of 758 RHVs in 693 different genes. By prioritizing these genes based on variant severity, loss-of-function intolerance and specific expression in the developing heart, we identified a set of 23 candidate disease genes. These candidate genes were significantly enriched for genes known to cause heart defects in recessive mouse models (P < 2.4e-06). In addition, we found a significant enrichment of cilia genes in both the initial set of 693 genes (P < 5.4e-04) and the 23 candidate disease genes (P < 5.2e-04). Functional investigation of ADCY6 in cell- and zebrafish-models verified its role in heart development. Our results confirm a significant role for cilia genes in recessive forms of CHD and suggest important functions of cilia genes in cardiac septation.

Financial Management Analysis in Early Marriage Families in Galis District, Pamekasan

Early marriage is a marriage that occurs at the age of under 19 years for both men and women. Financial management is one of the skills that must be possessed to manage the economy, especially the family economy. This study aims to describe and explain financial management in early marriage families in Galis Pamekasan District. The method used in this study is a descriptive qualitative method. The data used in this study uses primary data, namely direct observation and interviews with informants, as well as secondary data, namely from previous articles, and other literature sources. The results of this study obtained that financial management in early marriage families is more centered on the wife, meaning that the wife has more rights to manage finances more deeply than the husband. This is because the management of income, expenses, future planning, and debt management is more managed by the wife. Keywords : Early Marriage, Family, Financial Management

Linkages between consanguinity, pregnancy outcomes and offspring mortality in twenty-first century India.

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.

Niemann-Pick Disease: A case report

This case study’s major objective to explore the limitations of treatment and management arisen of having Niemann pick disease, due to poor prognosis or lack of early diagnosis. Mrs. Pinki, 30 years old female patient from Chuadanga, with the complaint of upper abdominal swelling for 6 months, generalized weakness for last 3 months, anorexia &amp; nausea for same duration, came to private chamber somewhere in Bangladesh, on 10th April 2023. She also complained generalized weakness for last 6 months associated with anorexia, nausea for same duration. Bone marrow examination confirmed the possible diagnosis of Niemann pick disease. Until her last follow up report, the patient was alive and clinically sound comparing to her previous condition. However, due to her lower socio-economic condition, she didn’t continue the follow ups and could not able to do Sphingomyelinase enzyme level according to the physician’s advice. Social awareness against consanguineous marriage &amp; adding enzyme estimation facilities can a revolutionary change in reducing the mortality rate of this disease.