Pathogenic variants of ADAM22 affecting either its biosynthesis and/or its interactions with either LGI1 and/or PSD-95 have been recently identified in individuals with developmental and epileptic encephalopathy. Here, we describe a girl with seizures, delayed psychomotor development, and behavioural disorder, carrying a homozygous variant in ADAM22 (NM_021723.5:c.2714C > T). The variant has a surprisingly high frequency in the Roma population of the Czech and Slovak Republic, with 11 of 213 (∼5.2%) healthy Roma individuals identified as heterozygous carriers. Structural in silico characterization revealed that the genetic variant encodes the missense variant p.S905F, which localizes to the PDZ-binding motif of ADAM22. Studies in transiently transfected mammalian cells revealed that the variant has no effect on biosynthesis and stability of ADAM22. Rather, protein-protein interaction studies showed that the p.S905F variant specifically impairs ADAM22 binding to PSD-95 and other proteins from a family of membrane-associated guanylate kinases, while it has only minor effect on ADAM22-LGI1 interaction. Our study indicates that a significant proportion of epilepsy in patients of Roma ancestry may be caused by homozygous c.2714C > T variants in ADAM22. The study of this ADAM22 variant highlights a novel pathogenic mechanism of ADAM22 dysfunction and reconfirms an essential role of interaction of ADAM22 with membrane-associated guanylate kinases in seizure protection in humans.

• Publication type
• Journal Article MeSH

A point mutation within exon 5 of beta-hexosaminidase alpha chain gene was identified earlier in a Puerto Rican patient with GM2-gangliosidosis B1 variant (the DN-allele) [K. Ohno and K. Suzuki: J. Neurochem. 50:316-318, 1988]. Oligonucleotide probes designed to detect either the normal or the DN-allele showed that four additional patients carried the same mutation. These patients were of Italian, French, Spanish, and English/Italian/Hungarian origin. Three of them, as well as our original patient, were compound heterozygotes with positive signals for both the mutant and normal probes, while the Spanish patient was positive only for the DN-allele. A patient from Czechoslovakia was negative for the DN-allele. Thus, the specific mutation originally found in the Puerto Rican patient has a surprisingly wide geographic and ethnic distribution. This mutation can account for the B1 variant phenotype in five of the six B1 variant patients so far examined.

• MeSH
• Alleles MeSH
• beta-N-Acetylhexosaminidases genetics   MeSH
• DNA Probes MeSH
• Exons MeSH
• G(M2) Ganglioside genetics   MeSH
• Gangliosidoses epidemiology   ethnology   genetics   MeSH
• Heterozygote MeSH
• Nucleic Acid Hybridization MeSH
• Humans MeSH
• Mutation MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, U.S. Gov't, P.H.S. MeSH
• Geographicals
• Czechoslovakia MeSH
• France MeSH
• Italy MeSH
• Hungary MeSH
• Germany MeSH
• Puerto Rico MeSH
• Spain MeSH
• United States MeSH

BACKGROUND: The Roma are a European ethnic minority threatened by several recessive diseases. Variants in MANBA cause a rare lysosomal storage disorder named beta-mannosidosis whose clinical manifestation includes deafness and mental retardation. Since 1986, only 23 patients with beta-mannosidosis and biallelic MANBA variants have been described worldwide. RESULTS: We now report on further 10 beta-mannosidosis patients of Roma origin from eight families in the Czech and Slovak Republics with hearing loss, mental retardation and homozygous pathogenic variants in MANBA. MANBA variant c.2158-2A>G screening among 345 anonymized normal hearing controls from Roma populations revealed a carrier/heterozygote frequency of 3.77%. This is about 925 times higher than the frequency of this variant in the gnomAD public database and classifies the c.2158-2A>G variant as a prevalent, ethnic-specific variant causing hearing loss and mental retardation in a homozygous state. The frequency of heterozygotes/carriers is similar to another pathogenic variant c.71G>A (p.W24*) in GJB2, regarded as the most frequent variant causing deafness in Roma populations. CONLCUSION: Beta-mannosidosis, due to a homozygous c.2158-2A>G MANBA variant, is an important and previously unknown cause of hearing loss and mental retardation among Central European Roma.

• MeSH
• beta-Mannosidosis * MeSH
• Ethnicity MeSH
• Deafness * genetics   MeSH
• Humans MeSH
• Minority Groups MeSH
• Hearing Loss * genetics   MeSH
• Roma * genetics   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Geographicals
• Czech Republic MeSH
• Slovakia MeSH

Východisko. Poměrně častá genetická varianta LHb podjednotky, která má i za následek změny v ose hypofýza- gonády, má různou prevalenci v rozdílných etnických populacích. Metody a výsledky. Frekvence výskytu variantní alely u nás byla určena analýzou LH u náhodně vybraného populačního vzorku v okrese Cheb, v němž bylo 257 osob (82 mužů a 175 žen) ve věku od 14 do 72 let. Variantní LH byl stanoven imunofluorescenční metodou ve dvou esejích, z nichž jedna zachytí jak divoký typ, tak variantní LH, druhá pouze divoký typ LH. Frekvence nosičství variantní alely pro LHb podjednotku byla 17,5 % (u mužů 12,2 % a u žen 20,6 %). Závěry. Prevalence variantní alely pro LHb podjednotku ve sledované oblasti západních Čech byla tedy blízká jiným středo- a severoevropským populacím.

Background. The relatively common genetic variant of LHb-subunit, resulting in changes of the pituitary-gonadal axis, displays different prevalence in various ethnic populations. Methods and Results. Frequency of occurrence of the variant allele in our country has been determined by analysis of LH in a randomly selected population group from the Cheb region, comprising of 257 subjects (82 men and 175 women) in the age from 14 to 72 years. The LH variant was determined by a novel immunofluorescence method, based on two assays, of which the first detected the wild type of the hormone and its variant, while the second was specific for the wild type of LH only. The frequency of carriers of the variant allele for LH-b-subunit amounted to 17.5 %, i.e. 12.2 % in males and 20.6 % in females. Conclusions. The prevalence of the variant allele for LH-b-subunit in the investigated region of West Bohemia was close to that of other Antral European and North European populations.

• MeSH
• Genetic Carrier Screening MeSH
• Adult MeSH
• Homozygote MeSH
• Corpus Luteum Hormones blood   MeSH
• Middle Aged MeSH
• Humans MeSH
• Mutation MeSH
• Prevalence MeSH
• Aged MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Comparative Study MeSH
• Geographicals
• Czech Republic MeSH

Hereditary spastic paraplegia (HSP or SPG) is a group of rare upper motor neuron diseases. As some ethnically-specific, disease-causing homozygous variants were described in the Czech Roma population, we hypotesised that some prevalent HSP-causing variant could exist in this population. Eight Czech Roma patients were found in a large group of Czech patients with suspected HSP and were tested using gene panel massively parallel sequencing (MPS). Two of the eight were diagnosed with SPG11 and SPG77, respectively. The SPG77 patient manifests a pure HSP phenotype, which is unusual for this SPG type. Both patients are compound heterozygotes for two different variants in the SPG11 (c.1603-1G>A and del ex. 16-18) and FARS2 (c.1082C>T and del ex.1-2) genes respectively; the three variants are novel. In order to find a potential ethnically-specific, disease-causing variant for HSP, we tested the heterozygote frequency of these variants among 130 anonymised DNA samples of Czech Roma individuals without clinical signs of HSP (HPS-negative). A novel deletion of ex.16-18 in the SPG11 gene was found in a heterozygous state in one individual in the HSP-negative group. Haplotype analysis showed that this individual and the patient with SPG11 shared the same haplotype. This supports the assumption that the identified SPG11 deletion could be a founder mutation in the Czech Roma population. In some Roma patients the disease may also be caused by two different biallelic pathogenic mutations.

• MeSH
• Child MeSH
• Adult MeSH
• Ethnicity genetics   MeSH
• Phenylalanine-tRNA Ligase genetics   MeSH
• Genetic Variation genetics   MeSH
• Heterozygote * MeSH
• Middle Aged MeSH
• Humans MeSH
• Mitochondrial Proteins genetics   MeSH
• Adolescent MeSH
• Young Adult MeSH
• Child, Preschool MeSH
• Proteins genetics   MeSH
• Pedigree MeSH
• Roma ethnology   genetics   MeSH
• Spastic Paraplegia, Hereditary diagnosis   ethnology   genetics   MeSH
• Check Tag
• Child MeSH
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Male MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Geographicals
• Czech Republic MeSH

Kardiovaskulární a renální onemocnění mají celosvětově signifikantní podíl na mortalitě a morbiditě. Obě onemocnění mají významné genetické pozadí a řada genů (např. geny pro apolipoprotein E a FTO) se nezávisle podílí na rozvoji obou onemocnění. Jedním z genů, jehož varianty jsou spojeny s rozvojem těchto onemocnění je i gen pro apolipoprotein L1. V genu se vyskytuje několik set polymorfizmů. Dosud publikované výsledky však ukazují, že rizikové varianty tohoto genu (označované převážně jako G1 a G2; kódované rs73885319/rs60910145 a rs71785313 polymorfizmy) jsou přísně etnicky specifické – vyskytují se pouze u Afričanů, a nikoli u Evropanů či Asiatů. Rizikové alely zvyšují riziko rozvoje renálního selhání 7–10krát a riziko kardiovaskulárního onemocnění přibližně 2násobně. Etnické rozdíly jsou výsledkem různého vývoje a odlišných selekčních tlaků (evoluční výhodou těchto alel je rezistence vůči spavé nemoci) působících na různé etnické skupiny a podtrhují nezbytnost cílených personalizovaných analýz beroucích v potaz tyto odlišnosti.

Cardiovascular and renal diseases are responsible for worldwide high mortality and morbidity. Both diseases have a significant genetic background, and a number of genes (eg. apolipoprotein E and FTO genes) are involved in the development of both diseases. Another gene, whose variants are associated with the development of these diseases is the apolipoprotein L1 (APOL1) gene. There are several hundred polymorphisms within the APOL1. However, the results reported so far show that the risk variants of this gene (mostly referred to as G1 and G2; encoded by rs73885319/rs60910145 and rs71785313 SNPs) are strictly ethnically specific – they occur exclusively in Africans, but not in Europeans or Asians. Risky alleles increase the risk of renal failure 7–10 times and doubled the risk of cardiovascular disease development. Ethnic differences are the result of diverse evolution and different selection pressures (the evolutionary advantage of these alleles is the resistance to sleeping sickness) affecting different ethnic groups and underline the need for targeted personalized analyses, taking into account these differences.

• MeSH
• Apolipoprotein L1 genetics   MeSH
• Ethnicity genetics   MeSH
• Cardiovascular Diseases * genetics   MeSH
• Humans MeSH
• Renal Insufficiency * genetics   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Research Support, Non-U.S. Gov't MeSH

Renal hypouricemia is a rare heterogeneous inherited disorder characterized by impaired tubular uric acid transport with severe complications, such as acute kidney injury. Type 1 and 2 are caused by loss-of-function mutations in the SLC22A12 and SLC2A9 gene, respectively. A cohort of 881 randomly chosen ethnic Roma from two regions in Eastern Slovakia and two regions in the Czech Republic participated. Genomic DNA was isolated from buccal swabs and/or from blood samples. The c.1245_1253del and c.1400C>T genotypes were determined using polymerase chain reaction with allele-specific primers in a multiplex arrangement and/or direct sequencing of exon 7 and 9. Allele frequencies and genotypes were tested for Hardy-Weinberg equilibrium using the Chi-square test. 25 subjects were heterozygous and three were homozygous for the c.1245_1253del, while 92 subjects were heterozygous and two were homozygous for the c.1400C>T. Moreover, two participants were compound heterozygotes. Frequencies of the c.1245_1253del and c.1400C>T variants were 1.87 and 5.56 %, respectively. Our finding confirms an uneven geographical and ethnic distribution of SLC22A12 mutant variants. We found that the c.1245_1253del and c.1400C>T variants were present in the Czech and Slovak Roma population at unexpectedly high frequencies. Renal hypouricemia should be kept in mind during differential diagnostic on Roma patients with low serum uric acid concentrations.

• MeSH
• Genetic Testing methods   MeSH
• Humans MeSH
• Urinary Calculi genetics   MeSH
• Polymerase Chain Reaction methods   MeSH
• Organic Anion Transporters genetics   MeSH
• Organic Cation Transport Proteins genetics   MeSH
• Retrospective Studies MeSH
• Roma genetics   MeSH
• Renal Tubular Transport, Inborn Errors genetics   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Multicenter Study MeSH
• Research Support, Non-U.S. Gov't MeSH
• Geographicals
• Czech Republic MeSH
• Slovakia MeSH

OBJECTIVE: To study the frequency and spectrum of CFTR gene variants in different ethnic groups of Kazakhstan. METHODS: We reviewed the records of 58 patients with cystic fibrosis. All the patients underwent molecular genetic analysis to reveal genotype-phenotype correlations. RESULTS: The median (IQR) age of the patients was 5.4 year (7 months, 18 year); 40% were diagnosed at the age of 5-10 year. The study identified 28 specific variants: p.Phe508del, the variant most common in the European population, was detected in 30 patients (51.7%). Variants other than p.Phe508del were revealed in 31% (21 patients). CONCLUSIONS: We found a number of specific variants characteristic of the Kazakhstani population. A pronounced regression of disease symptoms was detected in patients with mild mutations; whereas in patients with severe mutations, therapy produced very little effect.

• MeSH
• Cystic Fibrosis * epidemiology   genetics   MeSH
• Genotype MeSH
• Humans MeSH
• Mutation MeSH
• Cystic Fibrosis Transmembrane Conductance Regulator * genetics   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Geographicals
• Kazakhstan MeSH

Infrequent and rare genetic variants in the human population vastly outnumber common ones. Although they may contribute significantly to the genetic basis of a disease, these seldom-encountered variants may also be miss-identified as pathogenic if no correct references are available. Somatic and germline TP53 variants are associated with multiple neoplastic diseases, and thus have come to serve as a paradigm for genetic analyses in this setting. We searched 14 independent, globally distributed datasets and recovered TP53 SNPs from 202,767 cancer-free individuals. In our analyses, 19 new missense TP53 SNPs, including five novel variants specific to the Asian population, were recurrently identified in multiple datasets. Using a combination of in silico, functional, structural, and genetic approaches, we showed that none of these variants displayed loss of function compared to the normal TP53 gene. In addition, classification using ACMG criteria suggested that they are all benign. Considered together, our data reveal that the TP53 coding region shows far more polymorphism than previously thought and present high ethnic diversity. They furthermore underline the importance of correctly assessing novel variants in all variant-calling pipelines associated with genetic diagnoses for cancer.

• MeSH
• Genes, p53 genetics   MeSH
• Polymorphism, Single Nucleotide genetics   MeSH
• Humans MeSH
• Mutation, Missense genetics   MeSH
• Tumor Suppressor Protein p53 genetics   MeSH
• Neoplasms genetics   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

BACKGROUND: Cystic fibrosis (CF; OMIM #219700) is a common autosomal recessive disease caused by pathogenic variants (henceforward mutations) in the cystic fibrosis transmembrane conductance regulator gene (CFTR). The spectrum and frequencies of CFTR mutations vary among different populations. Characterization of the specific distribution of CFTR mutations can be used to optimize genetic counseling, foster reproductive choices, and facilitate the introduction of mutation-specific therapies. Chechens are a distinct Caucasian ethnic group of the Nakh peoples that originated from the North Caucasus. Chechens are one of the oldest ethnic groups in the Caucasus, the sixth largest ethnic group in the Russian Federation (RF), and constitute the majority population of the Chechen Republic (Chechnya). The spectrum of CFTR mutations in a representative cohort of Chechen CF patients and healthy individuals was analyzed. METHODS: Molecular genetic analysis of 34 CFTR mutations (representing approx. 80-85% of mutations in multiethnic CF populations of the RF) was performed in 32 CF patients from 31 unrelated Chechen families living in Chechnya. One hundred randomly chosen healthy Chechens were analyzed for the 15 most common "Russian" mutations. The clinical symptoms in Chechen CF patients with different CFTR genotypes were investigated. RESULTS: High frequencies of c.1545_1546delTA (p.Tyr515X; 1677delTA) (52 out of 64 CFTR alleles tested; 81.3%) and c.274G > A (p.Glu92Lys, E92K) (8/64, 12.5%) mutations were found. Twenty patients were homozygous for the c.1545_1546delTA mutation, and eight were compound heterozygous for the c.1545_1546delTA and c.274G > A mutations. Three carriers of the c.1545_1546delTA mutation were also found in the cohort of 100 apparently healthy Chechens (frequency - 0.015). The c.1545_1546delTA and c.274G > A mutations are linked to the same haplotype (22-7-16-13) of intragenic Short Tandem Repeat markers, i.e., IVS1CA, IVS6aGATT, IVS8CA, and IVS17bCA. CONCLUSIONS: The distribution of CFTR mutations in the Chechen CF population is unique regarding the high frequency of mutations c.1545_1546delTA and c.274G > A (more than 90% of the mutant alleles). The c.274G > A mutation is associated with a less severe course of CF than that observed in c.1545_1546delTA homozygotes. Testing for these two variants can be proposed as the first step of CF DNA diagnosis in the Chechen population.

• MeSH
• Point Mutation * MeSH
• Early Diagnosis MeSH
• Cystic Fibrosis ethnology   genetics   MeSH
• Child MeSH
• Gene Frequency MeSH
• Genetic Predisposition to Disease MeSH
• Infant MeSH
• Humans MeSH
• Adolescent MeSH
• Infant, Newborn MeSH
• Child, Preschool MeSH
• Cystic Fibrosis Transmembrane Conductance Regulator genetics   MeSH
• Sequence Deletion * MeSH
• Case-Control Studies MeSH
• Severity of Illness Index MeSH
• Check Tag
• Child MeSH
• Infant MeSH
• Humans MeSH
• Adolescent MeSH
• Male MeSH
• Infant, Newborn MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Geographicals
• Russia MeSH