Genetic forms of developmental delay and intellectual disability in the practice of the medical genetic consultation of Research Centre for Medical Genetics

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).

Growth Restriction and Genomic Imprinting-Overlapping Phenotypes Support the Concept of an Imprinting Network

Intrauterine and postnatal growth disturbances are major clinical features of imprinting disorders, a molecularly defined group of congenital syndromes caused by molecular alterations affecting parentally imprinted genes. These genes are expressed monoallelically and in a parent-of-origin manner, and they have an impact on human growth and development. In fact, several genes with an exclusive expression from the paternal allele have been shown to promote foetal growth, whereas maternally expressed genes suppress it. The evolution of this correlation might be explained by the different interests of the maternal and paternal genomes, aiming for the conservation of maternal resources for multiple offspring versus extracting maximal maternal resources. Since not all imprinted genes in higher mammals show the same imprinting pattern in different species, the findings from animal models are not always transferable to human. Therefore, human imprinting disorders might serve as models to understand the complex regulation and interaction of imprinted loci. This knowledge is a prerequisite for the development of precise diagnostic tools and therapeutic strategies for patients affected by imprinting disorders. In this review we will specifically overview the current knowledge on imprinting disorders associated with growth retardation, and its increasing relevance in a personalised medicine direction and the need for a multidisciplinary therapeutic approach.

Association of Assisted Reproductive Technology Treatments with Imprinting Disorders

Assisted reproductive technology (ART) is a broad field in infertility that encompasses different types of treatments. These revolutionary treatment methods aimed to aid infertile or subfertile couples. Treatment was expanded exponentially, as 1 to 3% of the births worldwide takes place with ART procedures. However, treatment is not flawless. Gametes and embryos are exposed to different chemicals and stress through treatment, which leads to disturbance in proper embryo development and results in prenatal and congenital anomalies. When compared with in-vivo development of gametes and preimplantation embryos in mice, in-vitro conditions during ART treatments have been suggested to disturb the gene expression levels, especially imprinted genes. Therefore, ART has been suggested to be associated with increased incidences of different imprinting disorders such as Beckwith–Wiedemann syndrome, Angelman syndrome, and Silver–Russell syndrome, as proved by different case reports and studies. This literature review aims to explain the association of imprinting disorders with this revolutionary treatment procedure.

Paternal Uniparental Disomy of the Entire Chromosome 20 in a Child with Beckwith-Wiedemann Syndrome

Epigenetic alterations at imprinted genes on different chromosomes have been linked to several imprinting disorders (IDs) such as Beckwith-Wiedemann syndrome (BWS) and pseudohypoparathyroidism type 1b (PHP1b). Here, we present a male patient with these two distinct IDs caused by two independent mechanisms-loss of methylation (LOM) at chromosome 11p15.5 associated with multi-locus imprinting disturbances (MLID and paternal uniparental disomy of chromosome 20 (patUPD20). A clinical diagnosis of BWS was made based on the clinical features of macrosomia, macroglossia, and umbilical hernia. The diagnosis of PHP1b was supported by the presence of reduced growth velocity and mild learning disability as well as hypocalcemia and hyperphosphatemia at 14 years of age. Molecular analyses, including genome-wide DNA methylation (Illumina 450k array), bisulfite pyrosequencing, single nucleotide polymorphism (SNP) array and microsatellite analysis, demonstrated loss of methylation (LOM) at IC2 on chromosome 11p15.5, and paternal isodisomy of the entire chromosome 20. In addition, imprinting disturbances were noted at the differentially methylated regions (DMRs) associated with DIRAS3 on chromosome 1 and PLAGL1 on chromosome 6. This is the first case report of PHP1b due to patUPD20 diagnosed in a BWS patient with LOM at IC2 demonstrating etiologic heterogeneity for multiple imprinting disorders in a single individual.