Familial hypercholesterolemia (FH) is caused by mutations in various genes, including the LDLR , APOB and PSCK9 genes; however, the spectrum of these mutations in Russian individuals has not been fully investigated. In the present study, mutation screening was performed on the LDLR gene and other FH-associated genes in patients with definite or possible FH, using next-generation sequencing. In total, 59 unrelated patients were recruited and sorted into two separate groups depending on their age: Adult (n=31; median age, 49; age range, 23-70) and children/adolescent (n=28; median age, 11; age range, 2-21). FH-associated variants were identified in 18 adults and 25 children, demonstrating mutation detection rates of 58 and 89% for the adult and children/adolescent groups, respectively. In the adult group, 13 patients had FH-associated mutations in the LDLR gene, including two novel variants [NM_000527.4: c.433_434dupG p.(Val145Glyfs*35) and c.1186G>C p.(Gly396Arg)], 3 patients had APOB mutations and two had ABCG5/G8 mutations. In the children/adolescent group, 21 patients had FH-causing mutations in the LDLR gene, including five novel variants [NM_000527.4: c.325T>G p.(Cys109Gly), c.401G>C p.(Cys134Ser), c.616A>C p.(Ser206Arg), c.1684_1691delTGGCCCAA p.(Pro563Hisfs*14) and c.940+1_c.940+4delGTGA], and 2 patients had APOB mutations, as well as ABCG8 and LIPA mutations, being found in different patients. The present study reported seven novel LDLR variants considered to be pathogenic or likely pathogenic. Among them, four missense variants were located in the coding regions, which corresponded to functional protein domains, and two frameshifts were identified that produced truncated proteins. These variants were observed only once in different patients, whereas a splicing variant in intron 6 (c.940+1_c.940+4delGTGA) was detected in four unrelated individuals. Previously reported variants in the LDLR, APOB, ABCG5/8 and LIPA genes were observed in 33 patients. The LDLR p.(Gly592Glu) variant was detected in 6 patients, representing 10% of the FH cases reported in the present study, thus it may be a major variant present in the Russian population. In conclusion, the present study identified seven novel variants of the LDLR gene and broadens the spectrum of mutations in FH-related genes in the Russian Federation.

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Intellectual development disorder (IDD) is characterized by a general deficit in intellectual and adaptive functioning. In recent years, there has been a growing interest in studying the genetic structure of IDD. Of particular difficulty are patients with non-specific IDD, for whom it is impossible to establish a clinical diagnosis without complex genetic diagnostics. We examined 198 patients with non-specific IDD from 171 families using whole-exome sequencing and chromosome microarray analysis. Hereditary forms of IDD account for at least 35.7% of non-specific IDD, of which 26.9% are monogenic forms. Variants in the genes associated with the BAF (SWI/SNF) complex were the most frequently identified. We were unable to identify phenotypic features that would allow differential diagnosis of monogenic and microstructural chromosomal rearrangements in non-specific IDD at the stage of clinical examination, but due to its higher efficiency, exome sequencing should be the diagnostic method of the highest priority study after the standard examination of patients with NIDD in Russia.

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Задержка психического развития (ЗПР) и умственная отсталость (УО) являются частыми причинами направления пациентов на медико-генетическое консультирование. Наблюдаемый в последние годы значительный рост числа нозологических форм моногенных и хромосомных болезней среди пациентов с ЗПР или УО медико-генетической консультации Медико-генетического научного центра отражает повышение эффективности диагностики наследственных форм данной патологии. Цели исследования: оценка долей клинически и/или лабораторно подтвержденных хромосомных, моногенных заболеваний и болезней геномного импринтинга, диагностированных у пациентов с ЗПР или УО; определение эффективности разных методов диагностики генетических форм ЗПР и УО; расчет сегрегационной частоты для оценки вклада моногенных форм с аутосомно-рецессивным и X-сцепленным рецессивным типами наследования в недифференцированные ЗПР и УО. Выборка включала 2350 пациентов с ЗПР или УО различных степеней тяжести и пациентов с диагнозом, предполагающим развитие ЗПР или УО по мере взросления, проконсультированных врачами-генетиками консультативного и научно-консультативного отделов Медико-генетического научного центра им. Бочкова в 2006, 2007, 2016 гг. и первой половине 2017 г. В исследуемый период (2006, 2007, 2016 и первая половина 2017 г.) отмечается тенденция к снижению доли хромосомной патологии среди всех пациентов выборки. В группе пациентов с ЗПР или УО с аномалиями хромосом с течением времени отмечается значительный рост доли структурной хромосомной патологии и снижение доли заболеваний, обусловленных изменением числа хромосом. Доля моногенных форм остается практически неизменной в исследуемый период. Внутри данной группы отмечается некоторый рост доли аутосомно-доминантной патологии. Доля пациентов с ЗПР или УО, обусловленных болезнями геномного импринтинга, достоверно различается в исследуемые годы, со временем отмечается тенденция к ее уменьшению. Доля только клинически установленных синдромов без лабораторного подтверждения значительно снижается в исследуемый период. Максимальная диагностическая эффективность среди лабораторных генетических методов показана для микросателлитного анализа, MLPA, хромосомного микроматричного анализа и секвенирования нового поколения. Developmental delay (DD) and intellectual disability (ID) are frequent reasons for referring patients for medical genetic counseling. A significant increase in the number of nosological forms of monogenic and chromosomal diseases among patients with DD or ID in medical genetic consultation of Bochkov Research Centre for Medical Genetics in recent years reflects an increase in its effectiveness in diagnosing this pathology. Purpose of the research: 1. To estimate the proportion of clinically and/or laboratory-confirmed chromosomal, monogenic, and genomic imprinting disorders diagnosed in patients with DD or ID consulted by geneticists from the consultation and scientific consulting departments of the Bochkov Research Centre for Medical Genetics in 2006, 2007, 2016, and the first half of 2017. 2. Determination of the effectiveness of different diagnostic methods of genetic forms DD and ID. 3. Calculation of segregation frequency to estimate the contribution of monogenic forms with autosomal recessive and X-linked recessive types of inheritance among undifferentiated cases of DD and ID. The sampling for the analysis included 2350 patients with DD or ID of varying severity, as well as patients with a diagnosis suggesting the development of DD or ID as they mature, consulted by geneticists from the consultation and scientific consulting departments of the Bochkov Research Centre for Medical Genetics in 2006, 2007, 2016, and the first half of 2017. During the research period (2006, 2007, 2016, and the first half of 2017), there was a decreasing trend in the proportion of chromosomal pathology among all patients of the sampling. Within the group of patients with DD or ID with chromosomal pathology, a significant increase in the proportion of structural chromosomal pathology and a decrease in the proportion of diseases caused by changes in the number of chromosomes is noted over time. The proportion of monogenic forms remains practically unchanged during the study period. Within this group, there is some increase in the share of AD pathology. The proportion of patients with DD or ID caused by genomic imprinting disorders varies significantly in the years studied, with a tendency to decrease over time. The proportion of only clinically identified syndromes without laboratory confirmation decreases significantly during the study period. The maximum diagnostic efficiency among laboratory genetic methods has been shown for microsatellite analysis, MLPA, chromosomal microarray analysis (CMA) and next generation sequencing (NGS).

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