Atypowe cechy fenotypowe u nosicieli nowej mutacji nonsens Q248X w genie HNF1B

Introduction: Hepatocyte transforming factor 1B-maturity onset diabetes mellitus of the young (HNF1B-MODY) is an autosomal dominant type of monogenic diabetes caused by a mutation in the gene encoding hepatocyte nuclear factor 1beta (HNF-1beta). The aim of this study was to determine if a HNF1B gene mutation was responsible for a dominantly inherited form of diabetes mellitus among the members of a three-generation Polish family. Material and methods: The index subject was a 13-year-old boy with metabolic syndrome, spina bifida occulta, posterior urethral valves, congenital ureteropelvic junction obstruction, and a family history of diabetes of autosomal dominant trait of inheritance. We performed clinical and laboratory examinations of his family and sequenced the HNF1B gene. Results: A novel Q248X mutation (nucleotide C to T transition at position 742 of the exon 3 of HNF1B gene, resulting in stop codon formation) was identified. Phenotypes of family members sharing this mutation are highly variable, and include previously known abnormalities of the urinary system and pancreas, diabetes mellitus of variable onset and severity, hyperinsulinaemia, insulin resistance, metabolic syndrome, elevated aminotransferases, hyperbilirubinemia, hyperamylasemia, short stature and cataracts. To the best of our knowledge, spina bifida occulta, pectus carinatum, and splenomegaly have not been previously reported. Conclusions: Our results broaden the spectrum of HNF1B gene mutations and HNF1B-MODY-related phenotypes. Wstęp: Cukrzyca HNF1B-MODY dziedziczona w sposób autosomalnie dominujący jest rodzajem cukrzycy monogenowej, którą powoduje mutacja w genie HNF1B (hepatocyte transforming factor 1B). Celem pracy było zbadanie czy mutacja w HNF1B jest przyczyną występowania cukrzycy w trzech pokoleniach polskiej rodziny. Materiał i metody: Przeprowadzono ocenę kliniczną i laboratoryjną oraz sekwencjonowanie genu HNF1B trzynastoletniego chłopca z zespołem metabolicznym, rozszczepem kręgosłupa, zastawkami cewki tylnej i wrodzonym zwężeniem moczowodu oraz obciążonym wywiadem rodzinnym w kierunku cukrzycy. Ze względu na wywiad rodzinny o autosomalnie dominującym sposobie dziedziczenia cukrzycy zbadano również członków jego rodziny. Wyniki: Stwierdzono obecność nowej mutacji Q248X będącej skutkiem przeniesienia nukleotydu C na miejsce T w pozycji 742 eksonu 3 genu HNF1B i powstaniem kodonu stop. Cechy fenotypowe członków rodziny będących nosicielami tej mutacji okazały być się bardzo zróżnicowane, a niektóre z nich takie jak spina bifida occulta, pectus carinatum i splenomegalia nie były dotychczas opisywane. Wnioski: Wyniki poszerzają spectrum mutacji genu HNF1B oraz związanych z nimi cech fenotypowych cukrzycy HNF1B-MODY

Immune dysregulation in patients with chromosome 18q deletions : searching for putative loci for autoimmunity and immunodeficiency

INTRODUCTION: Autoimmune disorders, IgA deficiency, and allergies seem to be common among individuals with 18q deletion syndrome [OMIM 601808]. We aimed to determine the prevalence, mechanism, and genetic background of autoimmunity, immune deficiency, and allergy in a cohort of patients with 18q deletions. MATERIAL AND METHODS: Medical registries and social media were used to recruit the patients. Microarray oligonucleotide comparative genomic hybridization (aCGH) (Agilent, Santa Clara, CA, USA) was performed in all patients to identify size and location of chromosome 18 deletion. Clinical evaluation and medical record collection were performed in each of the study participants. The history of autoimmune disorders, severe and/or recurrent infections, and symptoms of allergy were noted. Total immunoglobulin IgG, IgA, IgM, IgE, and IgG(1-4) serum levels were measured using nephelometry and ELISA methods. Lymphocyte T subset phenotyping was performed in 24 subjects from 18q del cohort. To predict the most promising candidate genes, we used the ENDEAVOUR—a free web resource for gene prioritization. RESULTS: 18q deletion was confirmed by means of array CGH analysis in 27 individuals, 15 (55.6%) females and 12 males, referred to the project by specialists in medical genetics, diabetology, or pediatric endocrinology between May 2015 and December 2019. The mean age at examination was 11.8 years (min–max: 4.0–33.5). Autoimmune disorders were present in 14/27 (51.8%) of the cohort. In eight of patients, symptoms of immune deficiency coexisted with autoimmunity. Allergy was reported in nine of 27 (33.4%) patients. Over 89% of patients presented with at list one type of immunoglobulin (IgA, IgM, IgG, IgE, and IgG(1-4)) deficiency and eight of 25 (32%) had abnormalities in at least two major immunoglobulin (IgG, IgA, IgM) measurements (CVID-like phenotype). Patients with 18q del exhibited a significantly decreased CD4, Treg FOXP3+, TregFOXP3+Helios+, and TemCD4 cell numbers in comparison with the control groups of 24 T1DM patients and 28 healthy controls. CONCLUSIONS: Patients with 18q deletions frequently suffer from autoimmune disorders, recurrent infections, and allergy due to immune dysregulation presenting with variable antibody deficiencies and T-regulatory cell deficiency (CD4+CD25+CD127lowFOXP3+). The spectrum of speculations regarding which gene might be responsible for such phenotype ranges from single gene haploinsufficiency to deletion of a cluster of immunogenes located distally to 18q21