Spectrum of JAG1 gene mutations in Polish patients with Alagille syndrome

Alagille syndrome (ALGS) is an autosomal dominant disorder characterized by developmental abnormalities in several organs including the liver, heart, eyes, vertebrae, kidneys, and face. The majority (90-94 %) of ALGS cases are caused by mutations in the JAG1 (JAGGED1) gene, and in a small percent of patients (∼1 %) mutations in the NOTCH2 gene have been described. Both genes are involved in the Notch signaling pathway. To date, over 440 different JAG1 gene mutations and ten NOTCH2 mutations have been identified in ALGS patients. The present study was conducted on a group of 35 Polish ALGS patients and revealed JAG1 gene mutations in 26 of them. Twenty-three different mutations were detected including 13 novel point mutations and six large deletions affecting the JAG1 gene. Review of all mutations identified to date in individuals from Poland allowed us to propose an effective diagnostic strategy based on the mutations identified in the reported patients of Polish descent. However, the distribution of mutations seen in this cohort was not substantively different than the mutation distribution in other reported populations

Cardiovascular involvement and prognosis in Loeys-Dietz syndrome

Background: Loeys-Dietz syndrome (LDS) is an inherited connective tissue disorder associated with aortic root enlargement and risk of thoracic aortic dissection (AD). Genetic examination is essential for diagnosis.Aims: The study aimed at analysis of clinical data on cardiovascular involvement and management of LDS patients.Methods: The study included carriers of LDS-associated genetic variants, identified between 2012 and 2022. Assessment of cardiovascular involvement was based on echocardiography and computed tomography angiography with quantitative assessment of arterial tortuosity. Involvement of other systems was also evaluated. We noted major cardiovascular events, including aortic events, defined as AD, elective aortic surgery, or otherwise unexplained sudden death.Results: Thirty-four patients from 15 families were included, and five identified variants were novel. Probands’ mean age was 41 years. Cardiovascular abnormalities, aortic involvement, aortic tortuosity, and tortuosity of cervical arteries were present in 79%, 71%, 68%, and 100% of carriers, respectively. First aortic events (9 A-type AD, 6 elective thoracic aortic surgeries, and one sudden death) occurred in 16 (47%) patients at a median age of 35 years. The youngest age at AD was 16 years, and 7 years for elective aneurysm repair. Second and third aortic events occurred in 9 and 4 patients, respectively. Eight patients (24%) experienced other major cardiovascular events. Aortic event-free survival was shorter in the presence of skin striae (P = 0.03), tended to be shorter in the presence of Marfanoid features (P = 0.06), and longer with TGFB2 variants (P = 0.06).Conclusions: LDS is associated with high burden of cardiovascular complications at a young age

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