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1.
Nature ; 629(8011): 376-383, 2024 May.
Article in English | MEDLINE | ID: mdl-38658749

ABSTRACT

From AD 567-568, at the onset of the Avar period, populations from the Eurasian Steppe settled in the Carpathian Basin for approximately 250 years1. Extensive sampling for archaeogenomics (424 individuals) and isotopes, combined with archaeological, anthropological and historical contextualization of four Avar-period cemeteries, allowed for a detailed description of the genomic structure of these communities and their kinship and social practices. We present a set of large pedigrees, reconstructed using ancient DNA, spanning nine generations and comprising around 300 individuals. We uncover a strict patrilineal kinship system, in which patrilocality and female exogamy were the norm and multiple reproductive partnering and levirate unions were common. The absence of consanguinity indicates that this society maintained a detailed memory of ancestry over generations. These kinship practices correspond with previous evidence from historical sources and anthropological research on Eurasian Steppe societies2. Network analyses of identity-by-descent DNA connections suggest that social cohesion between communities was maintained via female exogamy. Finally, despite the absence of major ancestry shifts, the level of resolution of our analyses allowed us to detect genetic discontinuity caused by the replacement of a community at one of the sites. This was paralleled with changes in the archaeological record and was probably a result of local political realignment.


Subject(s)
Archaeology , DNA, Ancient , Family Characteristics , Grassland , Pedigree , Adult , Female , Humans , Male , Archaeology/methods , Asia/ethnology , Cemeteries/history , Consanguinity , DNA, Ancient/analysis , Europe/ethnology , Family Characteristics/ethnology , Family Characteristics/history , Genomics , History, Medieval , Politics , Adolescent , Young Adult
2.
Sci Rep ; 14(1): 9230, 2024 04 22.
Article in English | MEDLINE | ID: mdl-38649688

ABSTRACT

With its high rate of consanguineous marriages and diverse ethnic population, little is currently understood about the genetic architecture of autism spectrum disorder (ASD) in Pakistan. Pakistan has a highly ethnically diverse population, yet with a high proportion of endogamous marriages, and is therefore anticipated to be enriched for biallelic disease-relate variants. Here, we attempt to determine the underlying genetic abnormalities causing ASD in thirty-six small simplex or multiplex families from Pakistan. Microarray genotyping followed by homozygosity mapping, copy number variation analysis, and whole exome sequencing were used to identify candidate. Given the high levels of consanguineous marriages among these families, autosomal recessively inherited variants were prioritized, however de novo/dominant and X-linked variants were also identified. The selected variants were validated using Sanger sequencing. Here we report the identification of sixteen rare or novel coding variants in fifteen genes (ARAP1, CDKL5, CSMD2, EFCAB12, EIF3H, GML, NEDD4, PDZD4, POLR3G, SLC35A2, TMEM214, TMEM232, TRANK1, TTC19, and ZNF292) in affected members in eight of the families, including ten homozygous variants in four families (nine missense, one loss of function). Three heterozygous de novo mutations were also identified (in ARAP1, CSMD2, and NEDD4), and variants in known X-linked neurodevelopmental disorder genes CDKL5 and SLC35A2. The current study offers information on the genetic variability associated with ASD in Pakistan, and demonstrates a marked enrichment for biallelic variants over that reported in outbreeding populations. This information will be useful for improving approaches for studying ASD in populations where endogamy is commonly practiced.


Subject(s)
Autism Spectrum Disorder , Exome Sequencing , Pedigree , Humans , Autism Spectrum Disorder/genetics , Pakistan , Male , Female , DNA Copy Number Variations/genetics , Genetic Predisposition to Disease , Child , Alleles , Consanguinity , Child, Preschool , Mutation , Homozygote
3.
J Clin Immunol ; 44(4): 101, 2024 Apr 17.
Article in English | MEDLINE | ID: mdl-38630413

ABSTRACT

PURPOSE: Inborn errors of immunity (IEI) are a heterogeneous group of diseases with variable clinical phenotypes. This study was conducted to describe the epidemiology, clinical presentations, treatment, and outcome of IEI in Jordanian children. METHODS: A retrospective data analysis was conducted for children under 15 years diagnosed with IEI from the pediatric Allergy, Immunology, and Rheumatology Division-based registry at Queen Rania Children's Hospital, Amman, Jordan, between 2010 and 2022. RESULTS: A total of 467 patients, 263 (56.3%) males and 204 (43.7%) females, were diagnosed with IEI. The mean age at symptom onset was 18 months (1 week to 144 months), a positive family history of IEI was reported in 43.5%, and the consanguinity rate was 47.9%. The most common IEI category was immunodeficiencies affecting cellular and humoral immunity at 33.2%, followed by predominantly antibody deficiencies at 16.9%. The overall median diagnostic delay (range) was 6 (0-135) months; patients with a positive family history of IEI had a statistically significant shorter diagnostic delay. Pulmonary and gastrointestinal clinical features were the most common at 55.2% and 45.6%, respectively. The overall mortality was 33.2%; the highest rate was reported in severe combined immunodeficiency at 56.2%. CONCLUSIONS: The high minimal estimated IEI prevalence at 16.2/100,000 Jordanian children compared to the regional and worldwide data, with the diversities in clinical presentation and distribution of IEI categories in our cohort point to unique features of IEI in Jordanian children, call for national registry establishment, regional and international collaborative networks.


Subject(s)
Delayed Diagnosis , Female , Male , Humans , Child , Infant , Jordan/epidemiology , Tertiary Care Centers , Retrospective Studies , Consanguinity
4.
Front Public Health ; 12: 1328300, 2024.
Article in English | MEDLINE | ID: mdl-38577288

ABSTRACT

Background: Marriage among cousins or close relatives, i.e., consanguinity, is prevalent in many parts of the world, especially the Muslim world. Across civilizations, cultural norms, religious beliefs, and economic factors affect consanguineous marriages (CMs); however, such marriages have social, genetic, and health repercussions. The present study investigated the university students' attitudes regarding CMs and factors influencing their attitudes at King Abdulaziz University (KAU), Jeddah, Kingdom of Saudi Arabia (KSA). Methods: This cross-sectional prospective study was conducted at KAU Jeddah in 2023. The questionnaire was distributed via electronic media (Emails, Facebook Messenger & WhatsApp). The convenience sampling technique was used to select participants, and descriptive and inferential statistics were used to analyze the data on SPSS-26. Results: A total of 1707 university students were part of the study (females, 1,198, 70.2%; males, 509, 29.8%). Almost half of the participants, 819 (48.0%), had parents with CMs. Most of the participants, 1,391 (81.5%), had CMs in the family. Half of the participants disagreed that parents consider marriage stable due to high compatibility and the same social relationship before and after marriage. About one-third of respondents said parents believe family marriage transmits cultural values and continuity and keeps wealth in the family. More than three-fourths of the participants stated that if marriage is arranged with first cousins, they will opt for genetic analysis (82.5%) and premarital counseling (85.2%). The personal attitudes of females (p < 0.001), undergraduate (p = 0.02), and health sciences students (p = 0.02) were more positive than their counterparts. Males (OR = 0.41; p < 0.001) and non-health sciences students (OR = 0.68; p = 0.01) were less likely to have significant positive attitudes than their counterparts. Among participants who had CM parents, males (OR = 0.397; p < 0.001) and non-health sciences students (OR = 0.60; p = 0.01) and urban residents (OR = 0.59; p = 0.01) had significantly lower odds of having a positive attitude than their counterparts. Conclusion: The practice of CMs is still prevalent in Saudi culture, with almost half of the participants having CM parents and the majority reporting these marriages in their families. Personal attitudes toward CMs were extremely positive. Most students prefer genetic testing and premarital counseling if marrying first cousins. Gender, faculty, parental income, and educational background influenced participants' attitudes.


Subject(s)
Students , Male , Female , Humans , Consanguinity , Cross-Sectional Studies , Saudi Arabia , Universities , Prospective Studies , Students/psychology , Surveys and Questionnaires
5.
Clin Res Hepatol Gastroenterol ; 48(5): 102335, 2024 May.
Article in English | MEDLINE | ID: mdl-38588792

ABSTRACT

BACKGROUND AND STUDY AIMS: In Morocco the prevalence of Wilson disease (WD) and the spectrum of mutations are not known. The aim of the present study was to estimate the prevalence of WD in Morocco, to evaluate the phenotype among a large cohort of WD patients, and to characterize ATP7B variants in a subgroup of WD patients. PATIENTS AND METHODS: We collected data from 226 patients admitted to five university hospital centers in Morocco between 2008 and 2020. The diagnosis was based on clinical manifestations, function tests and biochemical parameters. The genotype was characterized in 18 families diagnosed at the University Hospital Center of Marrakesh, by next generation sequencing. RESULTS: The mean annual prevalence in Morocco was 3.88 per 100,000 and the allele frequency was 0.15 %. Among the 226 patients included (121 males and 105 females), 196 were referred for a hepatic or neurological involvement and 30 were asymptomatic. The mean age at diagnosis was 13 ± 5.1 years (range: 5 - 42 years). Consanguinity was found in 63.3 % of patients. The mean duration of illness was 2.8 ± 1.9 years. Kayser-Fleischer rings were found in 131 (67.9 %) of 193 patients. Among the 196 symptomatic patients, 141/159 (88.7 %) had low serum ceruloplasmin (<0.2 g/L) and a high 24-hours urinary copper (>100 µg/day) was found in 173/182 (95.1 %) patients. The initial treatment was D-penicillamine in 207 patients, zinc acetate in five, zinc sulfate in five, and nine patients were not treated; 60/207 (29 %) patients have stopped treatment. A total of 72 patients died; the mortality rate was 31.9 %. Eight different ATP7B variants were identified among the 18 patients studied, of which two were novel (p.Cys1104Arg and p.Gln1277Hisfs*52), and six previously published (p.Gln289Ter, p.Cys305Ter, p.Thr1232Pro, p.Lys1020Arg, p.Glu583ArgfsTer25 and c.51+4A>T). All informative patients were homozygous for the disease-causing mutation. CONCLUSION: In Morocco, a high prevalence due to consanguinity and a high mortality rate due to the difficulty of diagnosis and lack of treatment were observed in WD patients. NGS sequencing identified new ATP7B variants in WD patients from Morocco.


Subject(s)
Copper-Transporting ATPases , Hepatolenticular Degeneration , Phenotype , Humans , Hepatolenticular Degeneration/genetics , Hepatolenticular Degeneration/epidemiology , Hepatolenticular Degeneration/diagnosis , Morocco/epidemiology , Male , Female , Adult , Adolescent , Child , Young Adult , Child, Preschool , Copper-Transporting ATPases/genetics , Mutation , Prevalence , Ceruloplasmin/analysis , Consanguinity , Genotype
7.
Clin Chem ; 70(5): 727-736, 2024 May 02.
Article in English | MEDLINE | ID: mdl-38592422

ABSTRACT

BACKGROUND: Cell-free fetal DNA exists within the maternal bloodstream during pregnancy and provides a means for noninvasive prenatal diagnosis (NIPD). Our accredited clinical service offers definitive NIPD for several autosomal recessive (AR) and X-linked conditions using relative haplotype dosage analysis (RHDO). RHDO involves next-generation sequencing (NGS) of thousands of common single nucleotide polymorphism (SNPs) surrounding the gene of interest in the parents and an affected or unaffected offspring to conduct haplotype phasing of the high- and low-risk alleles. NGS is carried out in parallel on the maternal cell-free DNA, and fetal inheritance is predicted using sensitive dosage calculations performed at sites where the parental genotypes differ. RHDO is not currently offered to consanguineous couples owing to the shared haplotype between parents. Here we test the expansion of RHDO for AR monogenic conditions to include consanguineous couples. METHODS: The existing sequential probability ratio test analysis pipeline was modified to apply to SNPs where both parents are heterozygous for the same genotype. Quality control thresholds were developed using 33 nonconsanguineous cases. The performance of the adapted RHDO pipeline was tested on 8 consanguineous cases. RESULTS: The correct fetal genotype was predicted by our revised RHDO approach in all conclusive cases with known genotypes (n = 5). Haplotype block classification accuracies of 94.5% and 93.9% were obtained for the nonconsanguineous and consanguineous case cohorts, respectively. CONCLUSIONS: Our modified RHDO pipeline correctly predicts the genotype in fetuses from consanguineous families, allowing the potential to expand access to NIPD services for these families.


Subject(s)
Consanguinity , Haplotypes , Noninvasive Prenatal Testing , Humans , Female , Pregnancy , Noninvasive Prenatal Testing/methods , Polymorphism, Single Nucleotide , High-Throughput Nucleotide Sequencing , Cell-Free Nucleic Acids/genetics , Prenatal Diagnosis/methods , Male
8.
Eur J Endocrinol ; 190(3): K43-K46, 2024 Mar 02.
Article in English | MEDLINE | ID: mdl-38465999

ABSTRACT

BACKGROUND: Homozygous mutations, 2 identical gene versions (alleles), 1 from each biological parent, are exceptional. Clinical descriptions of affected families, comprising few carriers only, are scattered throughout the literature, hindering evidence generation. METHODS: Included in this literature analysis were 5 RET families with ≥1 homozygous carrier and ≥3 heterozygous carriers per family. RESULTS: In consanguineous families with first-degree cousins, homozygotes presented with node-positive medullary thyroid cancer and pheochromocytoma in their mid-teens, whereas heterozygotes presented in their end-30s and early 40s. Homozygotes developed node-positive medullary thyroid cancer 27.4 years and pheochromocytoma 23 years earlier than heterozygotes. These age differences were smaller in the 15 families carrying founder mutation p.Leu666delinsAsnSer, whereas homozygotes developed node-positive medullary thyroid cancer in their mid-40s, 6 years earlier than heterozygotes in their early 50s. CONCLUSION: These results, limited in scope and size and modulated by extent of consanguinity, are consistent with moderate dose-response effects accelerating MEN2A development.


Subject(s)
Adrenal Gland Neoplasms , Carcinoma, Neuroendocrine , Multiple Endocrine Neoplasia Type 2a , Pheochromocytoma , Thyroid Neoplasms , Adolescent , Humans , Child , Multiple Endocrine Neoplasia Type 2a/genetics , Pheochromocytoma/genetics , Homozygote , Consanguinity , Phenotype , Proto-Oncogene Proteins c-ret/genetics , Pedigree , Thyroid Neoplasms/genetics , Adrenal Gland Neoplasms/genetics
9.
Pharm. pract. (Granada, Internet) ; 22(1): 1-4, Ene-Mar, 2024. ilus
Article in English | IBECS | ID: ibc-231370

ABSTRACT

The prevalence of 3-M syndrome remains unclear owing to its rarity and the limited number of reported cases in the medical literature. To date, approximately 100 cases of the disorder have been documented in MedlinePlus Genetics. Here, we present the first case study report from Jordan of a boy diagnosed with 3-M syndrome at 9 months of age via karyotyping. The patient exhibited distinct facial features, severe prenatal and postnatal growth retardation, and normal mental development. As rare genetic autosomal recessive mutations are common where consanguineous marriages are prevalent, raising awareness of such rare genetic diseases is critical. This paper aims to provide a case report on 3-M syndrome and a literature review. (AU)


Subject(s)
Humans , Infant , Fetal Growth Retardation , Consanguinity , Genetic Diseases, Inborn , Spine , Pelvis , Jordan
10.
Metab Brain Dis ; 39(4): 611-623, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38363494

ABSTRACT

Short-chain enoyl-CoA hydratase deficiency (ECHS1D) is a rare congenital metabolic disorder that follows an autosomal recessive inheritance pattern. It is caused by mutations in the ECHS1 gene, which encodes a mitochondrial enzyme involved in the second step of mitochondrial ß-oxidation of fatty acids. The main characteristics of the disease are severe developmental delay, regression, seizures, neurodegeneration, high blood lactate, and a brain MRI pattern consistent with Leigh syndrome. Here, we report three patients belonging to a consanguineous family who presented with mitochondrial encephalomyopathy. Whole-exome sequencing revealed a new homozygous mutation c.619G > A (p.Gly207Ser) at the last nucleotide position in exon 5 of the ECHS1 gene. Experimental analysis showed that normal ECHS1 pre-mRNA splicing occurred in all patients compared to controls. Furthermore, three-dimensional models of wild-type and mutant echs1 proteins revealed changes in catalytic site interactions, conformational changes, and intramolecular interactions, potentially disrupting echs1 protein trimerization and affecting its function. Additionally, the quantification of mtDNA copy number variation in blood leukocytes showed severe mtDNA depletion in all probands.


Subject(s)
DNA, Mitochondrial , Enoyl-CoA Hydratase , Child , Child, Preschool , Humans , Male , Computer Simulation , Consanguinity , DNA, Mitochondrial/genetics , Enoyl-CoA Hydratase/genetics , Enoyl-CoA Hydratase/deficiency , Mutation/genetics , Pedigree
11.
J Biosoc Sci ; 56(3): 445-458, 2024 May.
Article in English | MEDLINE | ID: mdl-38314634

ABSTRACT

Pakistan has a high burden of hereditary and congenital anomalies and their incidence rate almost doubles against the background of parental consanguinity. Consanguineous unions (CU) are customary in Pakistan and deeply rooted socio-cultural norms favour CU. This study aimed to elucidate the determinants and temporal change in CU in four northwestern populations of Pakistan. In a cross-sectional study, data on marital union types, bio-demographic factors, and paternal consanguinity were collected from 6,323 ever-married individuals in four districts of northwest Pakistan: Haripur, Muzaffarabad, Mansehra, and Shangla. We used descriptive statistics and multivariable logistic regression analysis. The CU were calculated to be 55%, and inbreeding coefficient F (ICF) was estimated to be 0.029. Eight factors, including district, rural origin, age of husband, occupational group of husband, literacy of husband, parental consanguinity, exchange marriage, and extended family type, were found to be significant predictors of consanguinity in the multivariable logistic regression analysis. The rate of consanguinity decreased significantly in the younger age categories of individuals. The rate of CU was seen to be declining over time and in marriages that started 'before 1980' and 'after 2010', respectively, and there was a decline in ICF from 0.030 to 0.027. These analyses also showed that the literacy rate improved, the average age at marriage increased, and the frequency of exchange marriages decreased over time. This study employs a sizable first-hand dataset to demonstrate a lowering CU rate in northwest Pakistan. It is anticipated that the burden of inherited and congenital anomalies may likely to diminish in the study populations along with the fall in ICF.


Subject(s)
Fathers , Marriage , Male , Humans , Consanguinity , Pakistan/epidemiology , Cross-Sectional Studies
12.
Clin Dysmorphol ; 33(2): 55-62, 2024 Apr 01.
Article in English | MEDLINE | ID: mdl-38410982

ABSTRACT

Biallelic mutations in UBE3B cause Kaufman oculocerebrofacial syndrome (KOS; OMIM 244450) with a wide range of clinical manifestations. In this study, we employed genetic analyses including homozygosity mapping, candidate gene sequencing, whole exome sequencing, and confirmatory Sanger sequencing on eight patients from three unrelated consanguineous families. Our analysis yielded three different novel variants in UBE3B : a missense substitution [NM_130466.4: c.2975C>T; (p.Pro992Leu)] in the HECT domain in family 1, a 3-bp deletion within exon 14 [c.1692_1694delCTC; (p.Ser565del)] leading to removal of a serine residue in family 2, and a splice donor site variant in intron eight of UBE3B (c.630 + 1G>T) in family 3. Blepharophimosis, telecanthus, ptosis, intellectual disability and abnormal lipid profile were similar to those found in previously reported KOS patients. Longitudinal follow-up revealed rather marfanoid body habitus of the patients in family 1. This study reports eight patients from Saudi Arabia with novel deleterious variants in UBE3B and adds to the phenotypic spectrum of KOS.


Subject(s)
Eye Abnormalities , Facies , Intellectual Disability , Limb Deformities, Congenital , Microcephaly , Humans , Intellectual Disability/genetics , Consanguinity , Microcephaly/genetics , Mutation , Pedigree , Ubiquitin-Protein Ligases/genetics
13.
DNA Repair (Amst) ; 136: 103633, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38422792

ABSTRACT

Inherited photosensitivity syndromes are a heterogeneous group of genetic skin disorders with tremendous phenotypic variability, characterized by photosensitivity and defective DNA repair, especially nucleotide excision repair. A cohort of 17 Iranian families with heritable photosensitivity syndromes was evaluated to identify their genetic defect. The patients' DNA was analyzed with either whole-exome sequencing or RNA sequencing (RNA-Seq). The interpretations of the genomic results were guided by genome-wide homozygosity mapping. Haplotype analysis was performed for cases with recurrent mutations. RNA-Seq, in addition to mutation detection, was also utilized to confirm the pathogenicity. Thirteen sequence variants, including six previously unreported pathogenic variants, were disclosed in 17 Iranian families, with XPC as the most common mutated gene in 10 families (59%). In one patient, RNA-Seq, as a first-tier diagnostic approach, revealed a non-canonical homozygous germline variant: XPC:c.413-9 T > A. The Sashimi plot showed skipping of exon 4 with dramatic XPC down-expression. Haplotype analysis of XPC:c.2251-1 G>C and XPC:1243 C>T in four families showed common haplotypes of 1.7 Mb and 2.6 Mb, respectively, denoting a founder effect. Lastly, two extremely rare cases were presented in this report: a homozygous UVSSA:c .1990 C>T was disclosed, and ERCC2-related cerebro-oculo-facio-skeletal (COFS) syndrome with an early childhood death. A direct comparison of our data with the results of previously reported cohorts demonstrates the international mutation landscape of DNA repair-related photosensitivity disorders, although population-specific differences were observed.


Subject(s)
Photosensitivity Disorders , Xeroderma Pigmentosum , Humans , Child, Preschool , Consanguinity , Xeroderma Pigmentosum/genetics , Extended Family , Iran , DNA-Binding Proteins/genetics , Mutation , DNA Repair , Photosensitivity Disorders/genetics , Xeroderma Pigmentosum Group D Protein , Carrier Proteins
14.
An Bras Dermatol ; 99(3): 380-390, 2024.
Article in English | MEDLINE | ID: mdl-38403552

ABSTRACT

BACKGROUND: Epidermolysis bullosa (EB) is a group of rare hereditary diseases, characterized by fragility of the skin and mucous membranes. Epidemiological data on EB in Brazil are scarce. OBJECTIVES: To describe epidemiological aspects of patients with EB diagnosed in the Dermatology Department of a tertiary hospital, from 2000 to 2022. METHODS: An observational and retrospective study was conducted through the analysis of medical records. The evaluated data included clinical form, sex, family history, consanguinity, age at diagnosis, current age, time of follow-up, comorbidities, histopathology and immunomapping, presence of EB nevi and squamous cell carcinomas (SCC), cause of and age at death. RESULTS: Of 309 patients with hereditary EB, 278 were included. The most common type was dystrophic EB (DEB), with 73% (28.4% dominant DEB, 31.7% recessive DEB and 12.9% pruriginous DEB). Other types were junctional EB with 9.4%, EB simplex with 16.5% and Kindler EB with 1.1%. Women accounted for 53% and men for 47% of cases. Family history was found in 35% and consanguinity in 11%. The mean age at diagnosis was 10.8 years and the current age was 26 years. The mean time of follow-up was nine years. Esophageal stenosis affected 14%, dental alterations affected 36%, malnutrition 13% and anemia 29%. During diagnostic investigation, 72.6% underwent histopathological examination and 92% underwent immunomapping. EB nevi were identified in 17%. Nine patients had SCC. Eleven patients died. STUDY LIMITATIONS: Insufficient data included to medical records, loss to follow-up, and unavailability of genetic testing. CONCLUSIONS: In this study, dystrophic EB predominated and the need for multidisciplinary care for comorbidities and complications was highlighted.


Subject(s)
Epidermolysis Bullosa , Tertiary Care Centers , Humans , Male , Female , Brazil/epidemiology , Tertiary Care Centers/statistics & numerical data , Retrospective Studies , Epidermolysis Bullosa/epidemiology , Epidermolysis Bullosa/pathology , Child , Adult , Young Adult , Child, Preschool , Adolescent , Middle Aged , Infant , Consanguinity , Sex Distribution , Age Distribution , Aged
15.
Mol Biol Rep ; 51(1): 302, 2024 Feb 14.
Article in English | MEDLINE | ID: mdl-38355773

ABSTRACT

BACKGROUND: Severe Combined Immunodeficiency (SCID) is an autosomal recessive inborn error of immunity (IEI) characterized by recurrent chest and gastrointestinal (GI) infections and in some cases associated with life-threatening disorders. METHODOLOGY AND RESULTS: This current study aims to unwind the molecular etiology of SCID and also extended the patients' phenotype associated with identified particular variants. Herein, we present 06 disease-causing variants identified in 07 SCID-patients in three different SCID related genes. Whole Exome Sequencing (WES) followed by Sanger Sequencing was employed to explore genetic variations. The results included identification of two previously reported heterozygous variants in homozygous form for the first time in RAG1gene [(p.Arg410Gln);(p.Arg737His)], followed by a recurrent variant (p.Trp959*) in RAG1, a novel variant in IL2RG (p.Asp48Lfs*24), a recurrent variant in IL2RG (p.Gly271Glu) and a recurrent variant in DCLRE1C (p.Arg191*) gene. CONCLUSION: To conclude, the immune-profiling and WES revealed two novel, two as homozygous state for the first time, and two recurrent disease causing variants contributing valuably to our existing knowledge of SCID.


Subject(s)
Severe Combined Immunodeficiency , Humans , Severe Combined Immunodeficiency/genetics , Consanguinity , Pakistan , Homozygote , Phenotype , Mutation/genetics , Pedigree
16.
Arch Dis Child ; 109(5): 428-431, 2024 Apr 18.
Article in English | MEDLINE | ID: mdl-38296613

ABSTRACT

BACKGROUND: The American Thoracic Society guidelines for the diagnosis of primary ciliary dyskinesia (PCD) consider the presence of a bi-allelic pathogenic variant confirmatory for the diagnosis of PCD, with genetic testing recommended when other confirmatory diagnostic tests are less accessible. We present our experience with genetic testing as first line with a proposed algorithm for high consanguinity populations. METHODS: Patients with a suspected diagnosis of PCD underwent genetic testing according to a diagnostic algorithm composed of three steps: (1) patients with a previously known causative familial/Bedouin tribal pathogenic variant completed direct testing for a single variant; (2) if the initial test was negative or there was no known pathogenic variant, a PCD genetic panel was completed; (3) if the panel was negative, whole exome sequencing (WES) was completed. RESULTS: Since the implementation of the protocol, diagnosis was confirmed by genetic testing in 21 patients. The majority of them were of Bedouin origin (81%) and had a positive history of consanguinity (65%). Nine patients (43%) had a sibling with a confirmed diagnosis. Most patients (15/21, 71%) were diagnosed by direct pathogenic variant testing and the remainder by genetic panel (19%) and WES (10%). Disease-causing variants were found in nine genes, with DNAL1 (24%) and DNAAF3, DNAAF5, ZMYND10 (14% each) as the most prevalent ones. CONCLUSIONS: In highly consanguineous regions, a stepwise genetic testing approach is recommended. This approach may be particularly useful in areas where the ability to obtain confirmatory diagnostic tests through other modalities is less accessible.


Subject(s)
Ciliary Motility Disorders , Genetic Testing , Humans , Consanguinity , Ciliary Motility Disorders/diagnosis , Ciliary Motility Disorders/genetics , Mutation
17.
Mol Biol Rep ; 51(1): 223, 2024 Jan 28.
Article in English | MEDLINE | ID: mdl-38281300

ABSTRACT

BACKGROUND: Infantile-onset inflammatory bowel disease (IOIBD) is a gastrointestinal inflammatory condition often associated with monogenic disorders and is frequently caused by Interleukin-10 deficiencies. This study aimed to identify the mutation responsible for IBD in an 8-year-old patient from an Iranian family with consanguineous parents. METHODS: Whole-exome sequencing (WES) was employed to identify disease-causing variations. Furthermore, we utilized integrated experimental data of HADDOCK molecular docking platform, including NMR spectroscopy, to characterize the mutant protein and elucidate the underlying functional mechanism of the identified mutation's pathogenicity. RESULTS: Our findings revealed a novel 19-bp deletion mutation (c.25_43del, p.Leu9CysfsTer15) in the IL10RB gene. Sanger sequencing confirmed that this variant was inherited in homozygous state within this family, marking the first mutation identified in exon 1 of this gene. Molecular docking simulation demonstrated that the mutant form of IL10RB exhibited reduced affinity for binding to the Interleukin-10 ligand, leading to disruptions in downstream cellular signaling pathways. CONCLUSIONS: The identification of this novel genetic variant as a causative factor for IOIBD highlights the clinical value of utilizing genetic testing, such as WES, as a reliable diagnostic approach for patients affected by this condition.


Subject(s)
Inflammatory Bowel Diseases , Interleukin-10 Receptor beta Subunit , Child , Humans , Consanguinity , Inflammatory Bowel Diseases/genetics , Interleukin-10 Receptor beta Subunit/genetics , Iran , Molecular Docking Simulation , Mutation
18.
Biodemography Soc Biol ; 69(1): 30-42, 2024.
Article in English | MEDLINE | ID: mdl-38261529

ABSTRACT

Consanguineous marriage is still a customary social phenomenon in Arab-Muslim communities. The aim of this study was to estimate the prevalence of consanguineous marriages in the Algerian population and to identify the socio-economic determinants associated with the practice of this form of union. This is a descriptive cross-sectional study included data for 21141 ever-married women aged 15-49 years, from the MICS6 Algeria (Multiple Indicator Cluster Survey database), conducted in 2019. Using a logistic regression model, we assessed the influence of socio-economic and geographical determinants on the practice of consanguineous marriages. The prevalence of consanguinity was 23.0% (95% CI: 22.4-23.6). According to multivariable binary logistic regression analysis, low level of education, early age at marriage (15-19; 20-30 years), rural area of residence, all geographical regions except the north-western territorial programming space, economic activity, and the lowest wealth index were the main determinants that assist in the prevalence of high rates of consanguineous marriages in Algeria. Considering these explanatory variables could help national health policy decision-makers to create and implement national preventive action plans that are intended alter behaviors attitudes toward preference of consanguineous marriages and, thus, reduce the burden of genetic disorders or congenital abnormalities associated with consanguinity.


Subject(s)
Consanguinity , Humans , Female , Algeria/epidemiology , Cross-Sectional Studies , Prevalence , Educational Status
19.
Neurogenetics ; 25(2): 79-83, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38240911

ABSTRACT

Narcolepsy with cataplexy is a complex disease with both genetic and environmental risk factors. To gain further insight into the homozygous HCRT-related narcolepsy, we present a case series of five patients from two consanguineous families, each harboring a novel homozygous variant of HCRT c.17_18del. All affected individuals exhibited severe cataplexy accompanied by narcolepsy symptoms during infancy. Additionally, cataplexy symptoms improved or disappeared in the majority of patients over time. Pathogenic variants in HCRT cause autosomal recessive narcolepsy with cataplexy. Genetic testing of the HCRT gene should be conducted in specific subgroups of narcolepsy, particularly those with early onset, familial cases, and a predominantly cataplexy phenotype.


Subject(s)
Alleles , Narcolepsy , Pedigree , Humans , Narcolepsy/genetics , Male , Female , Genes, Recessive , Orexins/genetics , Homozygote , Consanguinity , Child , Cataplexy/genetics , Adult , Phenotype , Adolescent , Mutation/genetics
20.
Mol Biol Rep ; 51(1): 104, 2024 Jan 15.
Article in English | MEDLINE | ID: mdl-38224417

ABSTRACT

BACKGROUND: Autosomal Recessive Primary Microcephaly (MCPH) is a rare, neurodevelopmental disorder associated with mild to severe mental retardation. It is characterized by reduced cerebral cortex that ultimately leads to reduction in skull size less than - 3 S.D below the mean for normal individuals having same age and sex. Till date, 30 known loci have been reported for MCPH. METHODS: In the present study, Sanger sequencing was performed followed by linkage analysis to validate the mutation in ASPM gene of the consanguineous Pakistani clans. Bioinformatics tools were also used to confirm the pathogenicity of the diseased variant in the gene. MRI scan was used to compare the brain structure of both the affected individuals (Aslam et al. in Kinnaird's 2nd International Conference on Science, Technology and Innovation, Lahore, 2023). RESULTS: Our study described a consanguineous family with two patients with a known ASPM (MCPH5) variant c.8508_8509delGA causing a frameshift mutation in exon 18 which located in calmodulin-binding IQ domain of the ASPM protein. The salient feature of this study is that a single variant led to significantly distinct changes in the architecture of brain of both siblings which is further confirmed by MRI results. The computation analysis showed that the change in the conservation of this residue cause this variant highly pathogenic. Carrier screening and genetic counselling were also remarkable features of this study (Aslam et al. in Kinnaird's 2nd International Conference on Science, Technology and Innovation, Lahore, 2023). CONCLUSION: This study explores the extraordinary influence of a single ASPM variant on divergent brain structure in consanguineous siblings and enable us to reduce the incidence of further microcephalic cases in this Pakistani family (Aslam et al. in Kinnaird's 2nd International Conference on Science, Technology and Innovation, Lahore, 2023).


Subject(s)
Brain , Siblings , Humans , Consanguinity , Pakistan , Brain/diagnostic imaging , Nerve Tissue Proteins
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