High Rate Of Parental Consanguinity Research Articles

Emerging Epidemiological Data on Rare Intellectual Disability Syndromes from Analyzing the Data of a Large Iranian Cohort.

Intellectual disability (ID) is a genetically heterogeneous condition, and so far, 1679 human genes have been identified for this phenotype. Countries with a high rate of parental consanguinity, such as Iran, provide an excellent opportunity to identify the remaining novel ID genes, especially those with an autosomal recessive (AR) mode of inheritance. This study aimed to investigate the most prevalent ID genes identified via next-generation sequencing (NGS) in a large ID cohort at the Genetics Research Center (GRC) of the University of Social Welfare and Rehabilitation Sciences. First, we surveyed the epidemiological data of 619 of 1295 families in our ID cohort, who referred to the Genetics Research Center from all over the country between 2004 and 2021 for genetic investigation via the NGS pipeline. We then compared our data with those of several prominent studies conducted in consanguineous countries. Data analysis, including cohort data extraction, categorization, and comparison, was performed using the R program version 4.1.2. We categorized the most common ID genes that were mutated in more than two families into 17 categories. The most common syndromic ID in our cohort was AP4 deficiency syndrome, and the most common non-syndromic autosomal recessive intellectual disability (ARID) gene was ASPM. We identified two unrelated families for the 36 ID genes. We found 14 genes in common between our cohort and the Arab and Pakistani groups, of which three genes (AP4M1, AP4S1, and ADGRG1) were repeated more than once. To date, there has been no comprehensive targeted NGS platform for the detection of ID genes in our country. Due to the large sample size of our study, our data may provide the initial step toward designing an indigenously targeted NGS platform for the diagnosis of ID, especially common ARID in our population.

Clinical and genetic profile of children with unexplained intellectual disability/developmental delay and epilepsy

ObjectiveThis study was conducted to evaluate the validity of performing whole exome sequencing in children with unexplained intellectual disability (ID), developmental delay (DD), and epilepsy. MethodsWe enrolled 61 Iranian children with unexplained DD/ID, and epilepsy with no etiologic diagnosis. 64 % of cases were male and 36 % were female, with a mean age of 6.2 years (range, 38 days to 15 years). Approximately 79 % of patients were born to consanguineous parents or had non-related parents from a highly inbred local region. Whole-exome sequencing analysis followed by Sanger sequencing was performed in all patients. ResultsPathogenic/likely pathogenic variants were identified in 59% (36/61) of patients, consisting of 26 novel and 14 known alterations. Variants of unknown significance were observed in 6.5 % (4/61) of patients. Variants in 28 genes have not been previously reported in Iranian patients with ID. Several additional phenotypes, mostly microcephaly, were common in 57.4 % of cases. Additionally, epilepsy was refractory in 40 % of patients. Three groups of brain anomalies consisting of brain dysgenesis, brain atrophy, and leukodystrophy were identified in our cohort. Mutations in genes implicated in cellular metabolic pathways were the most common, followed by ion channel/ion transporter and transcription pathways. DiscussionHigh-throughput DNA sequencing of the Iranian population with a high rate of parental consanguinity is a valuable strategy for identifying genetic etiology in children with unexplained ID/DD and epilepsy. Determining the genetic basis and most commonly involved pathways may help to identify novel genes and targeted antiepileptic treatments.

Effect of inbreeding on intellectual disability revisited by trio sequencing.

In outbred Western populations, most individuals with intellectual disability (ID) are sporadic cases, dominant de novo mutations (DNM) are frequent, and autosomal recessive ID (ARID) is very rare. Because of the high rate of parental consanguinity, which raises the risk for ARID and other recessive disorders, the prevalence of ID is significantly higher in near- and middle-east countries. Indeed, homozygosity mapping and sequencing in consanguineous families have already identified a plethora of ARID genes, but because of the design of these studies, DNMs could not be systematically assessed, and the proportion of cases that are potentially preventable by avoiding consanguineous marriages or through carrier testing is hitherto unknown. This prompted us to perform whole-exome sequencing in 100 sporadic ID patients from Iran and their healthy consanguineous parents. In 61 patients, we identified apparently causative changes in known ID genes. Of these, 44 were homozygous recessive and 17 dominant DNMs. Assuming that the DNM rate is stable, these results suggest that parental consanguinity raises the ID risk about 3.6-fold, and about 4.1 to 4.25-fold for children of first-cousin unions. These results do not rhyme with recent opinions that consanguinity-related health risks are generally small and have been "overstated" in the past.

Phenotypic and Genetic Characterization of a Cohort of Pediatric Wilson Disease Patients

BackgroundIn Egypt, Wilson disease seems to be under diagnosed and clinical data on large cohorts are limited. The aim of this study is to highlight the clinical, laboratory and genetic characteristics of this disease in our pediatric population as well as to report our experience with both treatment options and outcome.MethodsThe study included 77 patients from 50 unrelated families (62 were followed up for a mean period of 58.9 ± 6.4 months and 27 were asymptomatic siblings). Data were collected retrospectively by record analysis and patient interviews. Diagnosis was confirmed by sequencing of the ATP7B gene in 64 patientsResultsOur patients had unique characteristics compared to other populations. They had a younger age of onset (median: 10 years), higher prevalence of Kayser-Fleischer rings (97.6% in the symptomatic patients), low ceruloplasmin (93.5%), high rate of parental consanguinity (78.9%) as well as a more severe course. 71.42% of those on long term D-penicillamine improved or were stable during the follow up with severe side effects occurring in only 11.5%. Preemptive treatment with zinc monotherapy was an effective non-toxic alternative to D-penicillamine. Homozygous mutations were found in 85.7%, yet limited by the large number of mutations detected, it was difficult to find genotype-phenotype correlations. Missense mutations were the most common while protein-truncating mutations resulted in a more severe course with higher incidence of acute liver failure and neurological symptoms.ConclusionsEgyptian children with Wilson disease present with early Kayser-Fleischer rings and early onset of liver and neurological disease. The mutational spectrum identified differs from that observed in other countries. The high rate of homozygous mutations (reflecting the high rate of consanguinity) may potentially offer further insights on genotype-phenotype correlation

Abstract 5612: Identification of shared regions of genetic susceptibility to breast cancer in Arab and Jewish women with a family history of consanguinity

Abstract Background: Breast cancer is the most commonly diagnosed cancer in Israel, and a leading cause of death among women regardless of their ethnic origin. However, younger ages at diagnosis, larger primary tumor size, and lower 5-year survival rate have been reported among Arab women compared with the Jewish women. Arabs have a high rate of parental consanguinity, ranging from 25% to 60% in different countries in the Middle East. Consanguinity leads to a higher probability of sharing alleles identical-by-descent and increased risks for autosomal recessive disorders. Methods: Genome-wide analysis of germline DNA from 32 breast cancer patients and 26 first degree relatives was performed using the Affymetrix Human SNP Array 6.0 or the Illumina CytoSNP12 genotyping platform. Probands were screened for mutations in BRCA1 and BRCA2 to exclude common forms of inherited susceptibility. Genotype data were analyzed using PLINK to screen for runs of homozygosity of at least 500 kilobases. Results: Long runs of homozygosity were observed in five samples, including two consanguineous Arab and 3 Ashkenazi Jewish probands. The largest region of homozygosity was on chromosome 10q23.1-25.3 which harbors several important candidate genes, including the tumor suppressor gene PTEN. Conclusion: Preliminary analysis of breast cancer patients from consanguineous families of Arab or Jewish descent provide suggestive evidence of recessive susceptibility to breast cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5612. doi:10.1158/1538-7445.AM2011-5612

Clinico-epidemiologic features of oculocutaneous albinism in northeast section of Cairo – Egypt

Background Oculocutaneous albinism (OCA) is a genetically heterogeneous group of disorders characterized by the absence or reduced pigmentation of the skin, hair and eyes. To assess the clinico-epidemiologic features of different forms of OCA among Egyptian patients, we performed a retrospective study to determine the frequency, types, clinical presentation and associated genomic errors in albino patients and their relatives consulting the Genetics Clinic, Pediatric Hospital, Ain Shams University, Cairo, Egypt. Methods We used the outpatients index files to identify diagnosed cases of albinism referred from the dermatologic and ophthalmologic departments with different genodermatoses over 43 year period. We used specifically designed data collection protocol forms to extract epidemiological and clinical data from the patients medical records. These were entered into a computer database and analyzed using standard statistical software. Results The occurrence rate of albinism in our study was 20.4% of genodermatoses patients and 1 per 5843 patients attending the Pediatric hospital. Consanguineous marriage was reported among parents of 66.37% of patients and positive family history was reported in 46.01% of patients. Complete OCA was detected in 48.59% of patients, partial albinism in 41.59% of patients and syndromic albinism was detected in 7.96%. Associated genomic errors were detected in 36.28% of our albino patients and seventy one multiple mutant genomic errors were defined among relatives of thirty seven index families of oculocutaneous albinism patients. Conclusion To the best of our knowledge, this preliminary study is the first report of its kind from Egypt. The high rate of parental consanguinity among the parents of our Egyptian albino patients may account for the frequency of this genodermatosis in Egypt.

Clinico‐epidemiological features of primary hereditary ichthyoses in the Eastern province of Saudi Arabia

A total of 10 455 new dermatology patients were seen in the dermatology clinics of King Fahad Hospital of the University (KFHU), Al-Khobar, Saudi Arabia, between January 1990 and December 1995. We identified 71 patients with a histopathologically confirmed diagnosis of specific forms of primary hereditary ichthyoses (PHI). We have reviewed the epidemiological and clinical features of these patients. To document the epidemiological and clinical features of patients with PHI in the Eastern Province of Saudi Arabia. We used the dermatology out-patient department (OPD) logbooks to identify cases of PHI from new patients presenting with different dermatological problems over a 6-year period. We used specifically designed protocol forms to extract epidemiological and clinical data from the study patients' medical records. These were entered into a computer database and analyzed using standard statistical software. A total of 71 patients, 44 males and 27 females (male : female sex ratio of 1.63 : 1), were identified from a total of 10 455 new patients seen in our dermatology clinics between January 1990 and December 1995. The occurrence rate of PHI, in our clinics, was 0.67% or 7 per 1000 new dermatology cases. The clinical pattern of PHI showed that Icthyosis Vulgaris was the most common form seen, followed by Nonbullous Ichthyosiform Erythroderma. Thirty-one patients (44.7%) with Ichthyosis Vulgaris (IV) were seen: 12 patients (16.9%) with X-linked Recessive Ichthyosis (XLRI), four patients (5.6%) with Lamellar Ichthyosis (LI), three patients (4.2%) with Bullous Ichthyosiform Erythroderma (BIE) and 21 patients (29.6%) with Nonbullous Ichthyosiform Erythroderma (NBIE). There was a significantly high consanguinity rate in our patients (85%), and the family history was positive in 53 cases out of the 71 (75%). This preliminary study is the first report of its kind from Saudi Arabia and documents the clinico-epidemiological features of PHI patients in the Eastern Province. The high rate of parental consanguinity among our Saudi patients may account for the high proportion of patients with a positive family history. Consanguinity also probably explains why the most severe forms of PHI were seen in a significant number of new patients' siblings. These severe forms of PHI (Nonbullous Ichthyosiform Erythroderma, Bullous Ichthyosiform Erythroderma and Lamellar Ichthyosis) together constituted nearly 40% of all cases.

Spectrum of malformations of the hindbrain (cerebellum, pons, and medulla) in a cohort of children with high rate of parental consanguinity

We review 25 patients with a spectrum of hindbrain (cerebellum, pons, and medulla) malformations from a cohort of children with high parental consanguinity rate. Twenty-three of the 25 patients were born to consanguineous parents. The patients were classified in four groups. Eleven patients of 6 families had malformation of the hindbrain and midbrain with molar tooth sign (10 patients of 5 families with typical Joubert syndrome), 5 patients showed severe supratentorial anomalies in addition to the hindbrain malformations, 5 patients had pontocerebellar or cerebellar hypoplasia with anterior horn cell disease in the spinal cord (spinal muscular atrophy), and 4 patients showed malformations affecting predominantly the hindbrain without substantial involvement of other systems. A locus for Joubert syndrome was previously identified on chromosome 9q34.3 in two families, and a second locus on chromosome 11p12-q13.3 in another family. A third Joubert syndrome locus has been mapped at 6q23 and a mutation in the AHI1 gene at this site has been found recently in a further family from this cohort. Delineation of homogeneous subgroups of patients with hindbrain malformations and molecular genetic analysis of these groups may lead to identification of further loci, genes and mutations responsible for the malformations.

Clinico-epidemiological features of congenital nonbullous ichthyosiform erythroderma in the eastern province of Saudi Arabia.

A total of 10 455 new dermatology patients were seen in the dermatology clinics of King Fahd Hospital of the University (KFHU), Al-Khobar, Eastern Saudi Arabia, between January 1990 and December 1995. We identified 21 patients with a histopathologically confirmed diagnosis of congenital nonbullous ichthyosiform erythroderma (CNBIE). We have reviewed the epidemiological and clinical features of these patients. To document the epidemiological and clinical features of patients with CNBIE in eastern Saudi Arabia. We used the dermatology outpatient department (OPD) logbooks to identify diagnosed cases of CNBIE from new patients presenting with different dermatological problems over a 6-year period. We used specifically designed data-collection protocol forms to extract epidemiological and clinical data from the patients' medical records. These were entered into a computer database and analysed using standard statistical software. A total of 21 patients (five males, 16 females) with a male : female ratio of 0.31 : 1 were identified from a total of 10 455 new patients seen in our dermatology clinics over the study period. The occurrence rate of CNBIE in our clinics was 0.2%, or two per 1000 new dermatology cases. Nineteen (90%) of 21 CNBIE patients were born with collodion membranes. Eighty-one per cent of our patients had a positive family history of CNBIE. Consanguinity among the parents of our CNBIE patients was significantly high at 95%. To the best of our knowledge, this preliminary study is the first report of its kind from Saudi Arabia (documenting the clinico-epidemiological features of CNBIE patients in the Eastern Province). The high rate of parental consanguinity among the parents of our Saudi CNBIE patients may account for the high incidence rate of this genodermatosis in eastern Saudi Arabia. In comparison with results of other studies that reported a low occurrence rate of CNBIE among dermatology patients, our results were of a significantly higher rate.

Primary hereditary ichthyoses in the Eastern Province of Saudi Arabia.

Of 10,455 new dermatology patients seen at the Dermatology Clinic of King Fahad Hospital of the University, Al-Khobar, Saudi Arabia, between January 1990 and December 1995, the epidemiologic and demographic features of 71 patients, each with a histopathologically confirmed diagnosis of one specific type of primary hereditary ichthyosis (PHI), have been reviewed. To study and document the epidemiologic and demographic profiles of patients with PHI in the Eastern Province of Saudi Arabia. From the outpatient department dermatology logbooks, 71 patients with PHI, from 10,455 new cases with different dermatologic problems seen during the 5-year period, were included in this study. Using specially designed protocol forms, epidemiologic and demographic data were extracted from the medical records of the patients, entered into a computer, and analyzed using the SPSS program. Seventy-one patients with PHI, 44 males and 27 females (ratio, 1.63 : 1), were seen at our Dermatology Clinic between January 1990 and December 1995. The occurrence rate of PHI in our clinic is 0.67%, i.e. approximately 7 per 1000 new cases. The clinical pattern of PHI was as follows: 31 patients (44.7%) with ichthyosis vulgaris (IV), 12 (16.9%) with X-linked recessive ichthyosis (XLRI), four (5.6%) with lamellar ichthyosis (LI), three (4.2%) with bullous ichthyosiform erythroderma (BIE), and 21 (29.6%) with nonbullous ichthyosiform erythroderma (NBIE). IV was most common, followed by NBIE. Parental consanguinity was high (approximately 85%), and the family history was positive in 53 of the 71 cases (75%). This preliminary study has attempted to document the epidemiologic patterns of PHI patients in Saudi Arabia and, to our knowledge, this is the first report of its kind in this country. We found a high rate of parental consanguinity, a high percentage of patients with a positive family history, and many siblings affected by the severest forms of PHI, namely NBIE, BIE, and LI, which accounted for 39.4% of all cases of PHI.

Permanent neonatal diabetes mellitus: epidemiology, mode of presentation, pathogenesis and growth.

Permanent neonatal diabetes mellitus (PNIDDM) is a rare form of IDDM with unclear etiology and pathogenesis. We determined the incidence and prevalence rates and studied the clinical and biochemical features of PNIDDM in the Sultanate of Oman. The mean incidence rate during the study period from January 1989 to December 1994 was 1.788 +/- 0.82 per 100,000 live births per year. At the end of December 1994 the prevalence rate was 2.4 per 100,000 children below the age of 5 years. They constituted 41.6% of all cases of IDDM in this age group. Diarrhoea, fever, lethargy, poor feeding and failure to thrive were the most common presenting symptoms. Dehydration and tachypnoea were the most common signs. All patients who developed IDDM during the neonatal period had intrauterine growth retardation and 4.5 presented with diabetic ketoacidosis (plasma glucose 37 +/- 9 mmol/L, pH 7.12 +/- 0.1). Hypertriglyceridemia was a constant feature (19.4 +/- 4.8 mmol/L). They were products of consanguineous marriage with significantly high prevalence of IDDM and NIDDM in their family members. None of the infants had clinical or immunological evidence of congenital viral infection. Three of the five children had HLA-DR2, the diabetes resistance alleles. C-peptide secretion was absent during and after metabolic control of hyperglycemia in all the studied infants and none had circulating islet cell antibody at presentation or during the first year after diagnosis. Despite marked growth retardation at birth, there was a significant improvement of growth after initiating insulin therapy. Four of the 5 patients had normal developmental milestones, one had mild developmental delay following a severe and prolonged attack of hypoglycemia. None of the patients had exocrine pancreatic deficiency. In summary, the very high rate of parental consanguinity, occurrence in both sexes and in two siblings in the same family, absence of islet cell antibodies and the presence of HLA-DR2 loci in 3/5 of patients suggest that PNIDDM is a different disease process to standard IDDM in childhood and an autosomal recessive mode of transmission.

A High Rate (20%–30%) of Parental Consanguinity in Cytochrome-Oxidase Deficiency

By studying a large series of 157 patients, we found that complex I (33%), complex IV (28%), and complex I+IV (28%) deficiencies were the most common causes of respiratory chain (RC) defects in childhood. Truncal hypotonia (36%), antenatal (20%) and postnatal (31%) growth retardation, cardiomyopathy (24%), encephalopathy (20%), and liver failure (20%) were the main clinical features in our series. No correlation between the type of RC defect and the clinical presentation was noted, but complex I and complex I+IV deficiencies were significantly more frequent in cases of cardiomyopathy (P<.01) and hepatic failure (P<.05), respectively. The sex ratio (male/female) in our entire series was mostly balanced but was skewed toward males being affected with complex I deficiency (sex ratio R=1.68). Interestingly, a high rate of parental consanguinity was observed in complex IV (20%) and complex I+IV (28%) deficiencies. When parental consanguinity was related to geographic origin, an even higher rate of inbreeding was observed in North African families (76%, P<.01). This study gives strong support to the view that an autosomal recessive mode of inheritance is involved in most cases of mitochondrial disorders in childhood, a feature that is particularly relevant to genetic counseling for this devastating condition.

Liver disease in India.

One hundred and twenty-five children with chronic liver disease were seen in Pune in 13 months. Fifty-nine of them, aged 8-39 months, had Indian childhood cirrhosis histologically diagnosed. Their characteristics included an insidious onset of symptoms, a geographical clustering of cases in rural areas north-east of Pune, a high rate of parental consanguinity and affected siblings, and a very high hepatic copper concentration (790-6654 micrograms/g dry weight). Only 8 survived for 6 months, adverse prognostic features being jaundice, ascites, enlargement of the gall bladder, and severe anaemia at presentation. Clinical differentiation from other liver disorders in the same age group was clear in advanced cases but unreliable in earlier cases. Four asymptomatic siblings with hepatomegaly had a benign course. The need for non-invasive methods to diagnose early cases in the community is demonstrated. The other major diagnostic categories were: unresolved hepatitis (12); chronic active hepatitis (7); cryptogenic cirrhosis (6); neonatal hepatitis and biliary atresia (8).