scholarly journals The prevalence, genetic complexity and population-specific founder effects of human autosomal recessive disorders

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Qingyang Xiao ◽  
Volker M. Lauschke
Keyword(s):  
Molecular Genetics ◽  
Autosomal Recessive ◽  
Clinical Importance ◽  
Strongly Correlated ◽  
Founder Effects ◽  
Sequencing Data ◽  
Founder Mutations ◽  
Autosomal Recessive Disorders ◽  
Screening Programs ◽  
Significant Burden

AbstractAutosomal recessive (AR) disorders pose a significant burden for public health. However, despite their clinical importance, epidemiology and molecular genetics of many AR diseases remain poorly characterized. Here, we analyzed the genetic variability of 508 genes associated with AR disorders based on sequencing data from 141,456 individuals across seven ethnogeographic groups by integrating variants with documented pathogenicity from ClinVar, with stringent functionality predictions for variants with unknown pathogenicity. We first validated our model using 85 diseases for which population-specific prevalence data were available and found that our estimates strongly correlated with the respective clinically observed disease frequencies (r = 0.68; p < 0.0001). We found striking differences in population-specific disease prevalence with 101 AR diseases (27%) being limited to specific populations, while an additional 305 diseases (68%) differed more than tenfold across major ethnogeographic groups. Furthermore, by analyzing genetic AR disease complexity, we confirm founder effects for cystic fibrosis and Stargardt disease, and provide strong evidences for >25 additional population-specific founder mutations. The presented analyses reveal the molecular genetics of AR diseases with unprecedented resolution and provide insights into epidemiology, complexity, and population-specific founder effects. These data can serve as a powerful resource for clinical geneticists to inform population-adjusted genetic screening programs, particularly in otherwise understudied ethnogeographic groups.

scholarly journals The Molecular Genetics of Autosomal Recessive Nonsyndromic Intellectual Disability: a Mutational Continuum and Future Recommendations

2016 ◽  
Vol 80 (6) ◽  
pp. 342-368 ◽  
Author(s):  
Muzammil Ahmad Khan ◽  
Saadullah Khan ◽  
Christian Windpassinger ◽  
Muhammad Badar ◽  
Zafar Nawaz ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Molecular Genetics ◽  
Autosomal Recessive

scholarly journals Frequency of Important CYP450 Enzyme Gene Polymorphisms in the Iranian Population in Comparison with Other Major Populations: A Comprehensive Review of the Human Data

2021 ◽  
Vol 11 (8) ◽  
pp. 804
Author(s):  
Navid Neyshaburinezhad ◽  
Hengameh Ghasim ◽  
Mohammadreza Rouini ◽  
Youssef Daali ◽  
Yalda H. Ardakani
Keyword(s):  
Cytochrome P450 ◽  
Meta Analysis ◽  
Clinical Importance ◽  
Copy Number Variations ◽  
Iranian Population ◽  
Human Populations ◽  
Sequencing Data ◽  
Single Nucleotide Variants ◽  
Drug Dosing ◽  
Linkage Information

Genetic polymorphisms in cytochrome P450 genes can cause alteration in metabolic activity of clinically important medicines. Thus, single nucleotide variants (SNVs) and copy number variations (CNVs) in CYP genes are leading factors of drug pharmacokinetics and toxicity and form pharmacogenetics biomarkers for drug dosing, efficacy, and safety. The distribution of cytochrome P450 alleles differs significantly between populations with important implications for personalized drug therapy and healthcare programs. To provide a meta-analysis of CYP allele polymorphisms with clinical importance, we brought together whole-genome and exome sequencing data from 800 unrelated individuals of Iranian population (100 subjects from 8 major ethnics of Iran) and 63,269 unrelated individuals of five major human populations (EUR, AMR, AFR, EAS and SAS). By integrating these datasets with population-specific linkage information, we evolved the frequencies of 140 CYP haplotypes related to 9 important CYP450 isoenzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4 and CYP3A5) giving a large resource for major genetic determinants of drug metabolism. Furthermore, we evaluated the more frequent Iranian alleles and compared the dataset with the Caucasian race. Finally, the similarity of the Iranian population SNVs with other populations was investigated.

scholarly journals Consanguineous marriages in Finland and their implication for genetic disease

1995 ◽  
pp. 45-53
Author(s):  
Jaakko Ignatius
Keyword(s):  
Rural Areas ◽  
Genetic Disease ◽  
Autosomal Recessive ◽  
Genetic Diseases ◽  
Finnish Population ◽  
Autosomal Recessive Disorders ◽  
Consanguineous Marriages ◽  
The Mean ◽  
Autosomal Recessive Diseases ◽  
Recessive Disorders

The frequency of marriages contracted between individuals with close consanguinity has traditionally been low in Finland. In the 19th and early 20th centuries only 0.1-0.3% of all marriages were contracted between first-cousins (average kinship coefficient 0.0001-0.0002). In genealogical search, however, a remote consanguinity (often beyond 3rd cousins) is frequently found especially in the rural areas and the true level of inbreeding is higher. In Finland, several autosomal recessive diseases are known to be enriched in the population. This unique spectrum of genetic diseases is sometimes called »the Finnish Disease Heritage». To study the implication of close consanguinity for these disorders, information on consanguineous marriages closer than second-cousins was collected from 808 families representing 24 different »Finnish» autosomal recessive disorders. The mean rate of first-cousin marriages was 1.6% (0-20%). Consanguinity (parents second-cousins or closer) was found in 4.2% of the families. For comparison, in 160 families representing three »non-Finnish» autosomal disorders the corresponding figures were 1.9% and 2.5%, respectively. Although these figures are high when compared to the general Finnish population, it can be concluded that close consanguinity is not a significant factor of Finnish genetic diseases.

scholarly journals Leptin receptor deficiency: a systematic literature review and prevalence estimation based on population genetics

2020 ◽  
Vol 182 (1) ◽  
pp. 47-56 ◽  
Author(s):  
Lotte Kleinendorst ◽  
Ozair Abawi ◽  
Hetty J van der Kamp ◽  
Mariëlle Alders ◽  
Hanne E J Meijers-Heijboer ◽  
...  
Keyword(s):  
Literature Review ◽  
Systematic Literature Review ◽  
Early Onset ◽  
Autosomal Recessive ◽  
Leptin Receptor ◽  
Pituitary Hormone ◽  
Sequencing Data ◽  
Prevalence Estimation ◽  
Calculation Results ◽  
Number Of Individuals

Objective Leptin receptor (LepR) deficiency is an autosomal-recessive endocrine disorder causing early-onset severe obesity, hyperphagia and pituitary hormone deficiencies. As effective pharmacological treatment has recently been developed, diagnosing LepR deficiency is urgent. However, recognition is challenging and prevalence is unknown. We aim to elucidate the clinical spectrum and to estimate the prevalence of LepR deficiency in Europe. Design Comprehensive epidemiologic analysis and systematic literature review. Methods We curated a list of LEPR variants described in patients and elaborately evaluated their phenotypes. Subsequently, we extracted allele frequencies from the Genome Aggregation Database (gnomAD), consisting of sequencing data of 77 165 European individuals. We then calculated the number of individuals with biallelic disease-causing LEPR variants. Results Worldwide, 86 patients with LepR deficiency are published. We add two new patients, bringing the total of published patients to 88, of which 21 are European. All patients had early-onset obesity; 96% had hyperphagia; 34% had one or more pituitary hormone deficiencies. Our calculation results in 998 predicted patients in Europe, corresponding to a prevalence of 1.34 per 1 million people (95% CI: 0.95–1.72). Conclusions This study shows that LepR deficiency is more prevalent in Europe (n = 998 predicted patients) than currently known (n = 21 patients), suggesting that LepR deficiency is underdiagnosed. An important cause for this could be lack of access to genetic testing. Another possible explanation is insufficient recognition, as only one-third of patients has pituitary hormone deficiencies. With novel highly effective treatment emerging, diagnosing LepR deficiency is more important than ever.

Mendelian disorders causing hypertension

2010 ◽  
pp. 3071-3073
Author(s):  
Nilesh J. Samani ◽  
Maciej Tomaszewski
Keyword(s):  
Family History ◽  
Autosomal Recessive ◽  
Molecular Level ◽  
Age Of Onset ◽  
Severe Hypertension ◽  
Strong Family History ◽  
Autosomal Recessive Disorders ◽  
Mendelian Disorders ◽  
Recessive Disorders ◽  
Electrolyte Abnormalities

Several mendelian disorders with hypertension as the predominant manifestation have been characterized at the molecular level. Features that may suggest one of these very rare conditions include a young age of onset, moderate to severe hypertension, strong family history, consanguinity (for the autosomal recessive disorders), and electrolyte abnormalities, particularly of potassium (although this is not invariable)....

scholarly journals A Case of Salt-Wasting Congenital Adrenal Hyperplasia with Triple Homozygous Mutation: Review of Literature

2020 ◽  
Author(s):  
Maria Laura Iezzi ◽  
Gaia Varriale ◽  
Luca Zagaroli ◽  
Stefania Lasorella ◽  
Marco Greco ◽  
...  
Keyword(s):  
Congenital Adrenal Hyperplasia ◽  
Autosomal Recessive ◽  
Homozygous Mutation ◽  
Adrenal Hyperplasia ◽  
Phenotype Correlation ◽  
Hydroxylase Deficiency ◽  
Autosomal Recessive Disorders ◽  
Salt Wasting ◽  
21 Hydroxylase Deficiency ◽  
Recessive Disorders

AbstractCongenital adrenal hyperplasia (CAH) due to steroid 21-hydroxylase deficiency represents a group of autosomal recessive disorders characterized by impaired cortisol production due to altered upstream steroid conversions, subclassified as classic and nonclassic forms. The genotype–phenotype correlation is possible in the most frequent case but not in all. Despite in literature many mutations are known, there is the possibility of finding a new genetic pattern in patients with CAH.

Sign in / Sign up

Export Citation Format

Share Document