Background: Hereditary ophthalmic pathology is a genetically heterogeneous group of diseases that occur either as an isolated eye disorder or as a symptom of hereditary syndromes (chromosomal or monogenic). Thus, a diagnostic search in some cases of ophthalmic pathology can be time- and cost-consuming. The most challenging situation can arise when prenatal diagnosis is needed during an ongoing pregnancy. Case presentation: A family was referred to the Research Centre for Medical Genetics (RCMG) for childbirth risk prognosis at 7–8 week of gestation because a previous child, a six-year-old boy, has congenital aniridia, glaucoma, retinal detachment, severe psychomotor delay, and lack of speech and has had several ophthalmic surgeries. The affected child had been previously tested for PAX6 mutations and 11p13 copy number variations, which revealed no changes. Considering the lack of pathogenic changes and precise diagnosis for the affected boy, NGS sequencing of clinically relevant genes was performed for the ongoing pregnancy; it revealed a novel hemizygous substitution NM_000266.3(NDP):c.385G > T, p.(Glu129*), in the NDP gene, which is associated with Norrie disease (OMIM #310600). Subsequent Sanger validation of the affected boy and his mother confirmed the identified substitution inherited in X-linked recessive mode. Amniotic fluid testing revealed the fetus was hemizygous for the variant and lead to the decision of the family to interrupt the pregnancy. Complications which developed during the termination of pregnancy required hysterectomy due to medical necessity. Conclusions: Clinical polymorphism of hereditary ophthalmic pathology can severely complicate establishment of an exact diagnosis and make it time- and cost-consuming. NGS appears to be the method-of-choice in complicated cases, and this could substantially hasten the establishment of a diagnosis and genetic risk estimation.

Клинико-генетические характеристики ранней эпилептической энцефалопатии II типа, обусловленной мутациями в гене SCN2A

LAMA2-associated muscular dystrophy is a rare genetic disorder caused by pathogenic or likely pathogenic variants in the LAMA2 gene. The aim of this study is to characterize the spectrum of pathogenic/likely pathogenic variants in the LAMA2 gene among Russian patients, identify frequent pathogenic variants specific to this population, and estimate the prevalence of this disorder in Russia. Data were collected and analyzed from patients with confirmed diagnoses of LAMA2-associated muscular dystrophy using various molecular genetic methods in research centers from 2008 to 2024. Data were obtained from 90 unrelated patients with LAMA2-associated muscular dystrophy, out of which 83 presented with the more severe form, MDC1A1, while seven had milder form of LAMA2-associated muscular dystrophy. The most common pathogenic variants identified were nonsense mutations (40% of cases), followed by frameshift variants (29.3%), splicing variants (21.4%), gross deletions (5.3%), and missense variants (4%). It is worth noting that missense variants were found exclusively in patients with the milder form of LAMA2-associated muscular dystrophy. The most prevalent identified pathogenic variant was c.7536del (15%), characteristic of Slavic populations with an established founder effect. Additionally, a common pathogenic variant, c.8245-2A>G, was found predominantly in Kazan Tatars. The estimated prevalence of LAMA2-associated muscular dystrophy in Russia is approximately 1 in 117,700.

Early infantile epileptic encephalopathies (EIEE) are a group of disorders characterized by pharmacoresistant epileptic seizures manifesting in infancy and leading to psychomotor retardation. The most common genetic variant with X-linked dominant inheritance is type 2 EIEE associated with CDKL5 gene mutations. We evaluated the prevalence of this type of EIEE among Russian patients (n = 148) with epileptic seizures manifesting in infancy and analyzed their clinical and genetic characteristics. We performed exome sequencing for all patients; 15 (10 %) of them (aged between 2 months and 5 years) were found to have CDKL5 gene mutations and were, therefore, diagnosed with type 2 EIEE. The results of correlation analysis suggest that the severity of clinical manifestations of type 2 EIEE is largely determined by the location of mutations affecting the function of the protein encoded by this gene. This is important to ensure better understanding of type 2 EIEE etiology and predict it severity in patients with different allelic variants.

Introduction. A heterogeneous group of hereditary spastic paraplegias (HSP) with known causative genes, alongside the predominant autosomal dominant ones, includes numerous and diagnostically more complex autosomal recessive (AR) forms with diverse phenotypes. Massive parallele sequencing (MPS) techniques are widely used in HSP diagnosis. The aim of the study was to determine the clinical and molecular genetic characteristics of two AR-HSPs — SPG11 and SPG15 — in Russia based on the first study of HSP using MPS. Materials and methods. We examined 8 unrelated Russian families: seven with SPG11 and one with SPG15. Clinical and molecular analysis and multiplex ligation-dependent probe amplification (MLPA) were used. Results. SPG11, diagnosed in seven families, was the most common AR form, accounting for 5.1% of the total group of 120 families with verified HSP (4th common) and 30.5% of the AR-HSP subgroup. Three of the nine identified SPG11 mutations have not been previously described; 2 families had identical genotypes, with one of the allelic mutations consisting of a large duplication; one previously described mutation was detected three times. Two patients had an atypical late onset, six cases had complicating concomitant symptoms, such as ataxia and/or dysarthria, cognitive impairment, while 3 out of 6 patients showed thinning of the corpus callosum on MRI. SPG15 was diagnosed in one patient at 13 years; two new mutations were found in the ZFYVE26 gene with a reading frame shift in the compound heterozygous state. Clinical phenotype in this patient included progressive cognitive decline in addition to spastic paraparesis; there was no macular degeneration typical (but not mandatory) of SPG15 up to the age of 17 years (according to follow-up data). Conclusion. In a large group of patients in Russia, AR-HSP was represented by 12 different forms, with SPG11 being the most frequent and SPG15 also being present. A total of 11 mutations were found in the genes of both forms, 5 of which had not been previously described. Two complicated forms of HSP had a similar clinical presentation and were difficult to diagnose. MPS methods are indispensable in diagnosing diseases with pronounced genetic heterogeneity, such as HSP. Cases with major gene rearrangements confirm the importance of combining MPS with MLPA.