We report our results of 1000 diagnostic WES cases based on 2819 sequenced samples from 54 countries with a wide phenotypic spectrum. Clinical information given by the requesting physicians was translated to HPO terms. WES processes were performed according to standardized settings. We identified the underlying pathogenic or likely pathogenic variants in 307 families (30.7%). In further 253 families (25.3%) a variant of unknown significance, possibly explaining the clinical symptoms of the index patient was identified. WES enabled timely diagnosing of genetic diseases, validation of causality of specific genetic disorders of PTPN23, KCTD3, SCN3A, PPOX, FRMPD4, and SCN1B, and setting dual diagnoses by detecting two causative variants in distinct genes in the same patient. We observed a better diagnostic yield in consanguineous families, in severe and in syndromic phenotypes. Our results suggest that WES has a better yield in patients that present with several symptoms, rather than an isolated abnormality. We also validate the clinical benefit of WES as an effective diagnostic tool, particularly in nonspecific or heterogeneous phenotypes. We recommend WES as a first-line diagnostic in all cases without a clear differential diagnosis, to facilitate personal medical care.

The transcription factor BCL11B plays an essential role in the development of central nervous system and T cell differentiation by regulating the expression of numerous genes involved in several pathways. Monoallelic defects in the BCL11B gene leading to loss-of-function are associated with a wide spectrum of phenotypes, including neurological disorders with or without immunological features and susceptibility to hematological malignancies. From the genetic point of view, the landscape of BCL11B mutations reported so far does not fully explain the genotype-phenotype correlation. In this review, we sought to compile the phenotypic and genotypic variables associated with previously reported mutations in this gene in order to provide a better understanding of the consequences of deleterious variants. We also highlight the importance of a careful evaluation of the mutation type, its location and the pattern of inheritance of the variants in order to assign the most accurate pathogenicity and actionability of the genetic findings.

Common variable immunodeficiency (CVID) is an antibody immunodeficiency with a wide variety of clinical and immunological manifestations, and whose genetic cause is found in about 25% of diagnosed cases. Giardia lamblia is one of the main causes of gastrointestinal infections in CVID. 5-Nitroimidazoles are the most used first-line treatment, but nitroimidazole-refractory giardiasis is increasing. Nevertheless, only a few cases of refractory giardiasis in CVID have been reported. This study aimed to determine the incidence of Giardia infection in our CVID cohort, shows our management experience and describes patients’ phenotypic features. Clinical data collection, immunological, immunogenetics and microbiology assays were performed, and previous cases of giardiasis in CVID were reviewed. The incidence of symptomatic giardiasis was 12.9%. The main immunological features were undetectable or decreased IgA levels and reduced switched memory B cells. A probable PTEN pathogenic variant was detected in one. Three patients responded to metronidazole but suffered reinfections, and one was a refractory giardiasis eradicated with innovative quinacrine plus paromomycin combination. This work could contribute to the decision-making and therapeutic management of future patients with CVID and giardiasis, highlighting the importance of the early detection and treatment of infections in patients with CVID to ensure a good quality of life.

Alport syndrome (AS) is a clinically and genetically heterogeneous disorder with a wide phenotypic spectrum, onset, and progression. X-linked AS (XLAS) and autosomal recessive AS (ARAS) are severe conditions, whereas the severity of autosomal dominant AS (ADAS) may vary from benign familial hematuria to progressive renal disease with extra-renal manifestations. In this study, we collated information from the literature and analyzed a cohort of 317 patients with ADAS carrying heterozygous disease-causing mutations in COL4A3/4 including four patients from two unrelated families who carried two novel variants in COL4A3. Regarding the age of onset of the disease, 80% of patients presented urinalysis alterations (microhematuria, hematuria, and/or proteinuria) before the age of 40 years. The cumulative probability of suffering adverse renal events was mainly observed between 30 and 70 years, without statistical differences between COL4A3 and COL4A4. We observed statistically significant differences between the sexes in the age of developing ESKD in cases affected by mutations in COL4A3/4 (p value = 0.0097), suggesting that males begin experiencing earlier deterioration of renal function than women. This study supports the importance of follow-up in young patients who harbor pathogenic mutations in COL4A3/4. We update the knowledge of ADAS, highlighting differences in the progression of the disease between males and females.

Background and Aims: Common variable immunodeficiency (CVID) comprises a group of diseases with heterogeneous clinical and immunological manifestations. Several mutations have been identified in genes encoding proteins essential for immune function. Our aim was to phenotypically and genotypically characterize a patient diagnosed with CVID and study his response to the SARS-CoV-2 vaccine. Methods: We performed a next-generation sequencing analysis, a CMIA, and an ELISA to analyze the humoral and cellular response to the SARS-CoV-2 vaccine, respectively. We also employed flow cytometry and immunoturbidimetry to assess the patient’s global immune status. Results: We found a low humoral but positive cellular response to the SARS-CoV-2 vaccine. NGS screening revealed a transition from guanine to adenine at position c.485 of the IKZF1 gene in heterozygosity, giving rise to the R162Q variant, which was not present in his parents. Conclusions: The R162Q variant of the IKZF1 gene has been associated with CVID type 13, but always with an autosomal dominant inheritance with high penetrance. Therefore, we present for the first time a case of CVID associated with a de novo heterozygous R162Q variant in the IKZF1 gene in a patient with a low humoral immune response to the complete COVID-19 vaccination program.