КЛИНИКО-ГЕНЕТИЧЕСКАЯ ХАРАКТЕРИСТИКА СИНДРОМА ЯНСЕН-ДЕ ФРИС, ОБУСЛОВЛЕННОГО ГЕТЕРОЗИГОТНЫМИ МУТАЦИЯМИ В ГЕНЕ PPM1D

Abstract

Jansen-de Vries syndrome is a rare hereditary autosomal dominant disease caused by pathogenic variants in the PPM1D gene. To date, 18 cases of this syndrome have been described in the world. In all cases, heterozygous mutations were identified that arose de novo in the last or penultimate exons of the gene, leading to protein truncation. All observed patients had muscle hypotonia, delayed motor and speech development, intellectual and behavioral disorders, an increased pain threshold, and a peculiar phenotype. Objective of the research: to reveal clinical genetic signs of new cases of a rare syndromic form and to identify additional clinical and laboratory features that characterize Jansen-de Vries syndrome. The article presents observations of two patients with Jansen-de Vries syndrome, first diagnosed in the Russian Federation. Children underwent routine laboratory and instrumental examinations, repeated consultations with a neurologist, geneticist, ophthalmologist, cardiologist and orthopedist. The diagnosis was made by full exome sequencing. A comparison of the identified cases with those described in the literature is performed. The observed girls from two unrelated families showed characteristic clinical manifestations, as in patients previously presented in the foreign literature: muscle hypotension, delayed motor and psycho-speech development, small hands and feet. Additionally, the first child had a prolonged course of neonatal meningitis and a low level of immunoglobulin A, the second had unilateral ptosis, congenital stridor. The de novo mutations found were confirmed by Sanger sequencing. A previously undescribed pathogenic variant c.1225del (p.Met409Ter) in the penultimate exon of the PPM1D gene was detected in the first child of 10 months. In the second child, a previously established pathogenic variant c.1270dupG (p.Glu424fs) was found in the last exon of this gene. Conclusion: the work presents the first domestic observations confirming the presence of characteristic clinical and genetic manifestations of the Jansen-de Vries syndrome. In addition, a previously undescribed pathogenic variant c.1225del (p.Met409Ter) was revealed in the penultimate exon of the PPM1D gene. In one of the observed children, features of humoral immunity were found, which may also be characteristic of this pathology.