Loss-of-function variants in exon 4 of TAB2 cause a recognizable multisystem disorder with cardiovascular, facial, cutaneous, and musculoskeletal involvement.

PURPOSE: This study aimed to describe a multisystemic disorder featuring cardiovascular, facial, musculoskeletal, and cutaneous anomalies caused by heterozygous loss-of-function variants in TAB2. METHODS: Affected individuals were analyzed by next-generation technologies and genomic array. The presumed loss-of-function effect of identified variants was assessed by luciferase assay in cells transiently expressing TAB2 deleterious alleles. In available patients' fibroblasts, variant pathogenicity was further explored by immunoblot and osteoblast differentiation assays. The transcriptomic profile of fibroblasts was investigated by RNA sequencing. RESULTS: A total of 11 individuals from 8 families were heterozygotes for a novel TAB2 variant. In total, 7 variants were predicted to be null alleles and 1 was a missense change. An additional subject was heterozygous for a 52 kb microdeletion involving TAB2 exons 1 to 3. Luciferase assay indicated a decreased transcriptional activation mediated by NF-κB signaling for all point variants. Immunoblot analysis showed a reduction of TAK1 phosphorylation while osteoblast differentiation was impaired. Transcriptomic analysis identified deregulation of multiple pleiotropic pathways, such as TGFß-, Ras-MAPK-, and Wnt-signaling networks. CONCLUSION: Our data defined a novel disorder associated with loss-of-function or, more rarely, hypomorphic alleles in a restricted linker region of TAB2. The pleiotropic manifestations in this disorder partly recapitulate the 6q25.1 (TAB2) microdeletion syndrome and deserve the definition of cardio-facial-cutaneous-articular syndrome.

Chiari 1 malformation and exome sequencing in 51 trios: the emerging role of rare missense variants in chromatin-remodeling genes.

Type 1 Chiari malformation (C1M) is characterized by cerebellar tonsillar herniation of 3-5 mm or more, the frequency of which is presumably much higher than one in 1000 births, as previously believed. Its etiology remains undefined, although a genetic basis is strongly supported by C1M presence in numerous genetic syndromes associated with different genes. Whole-exome sequencing (WES) in 51 between isolated and syndromic pediatric cases and their relatives was performed after confirmation of the defect by brain magnetic resonance image (MRI). Moreover, in all the cases showing an inherited candidate variant, brain MRI was performed in both parents and not only in the carrier one to investigate whether the defect segregated with the variant. More than half of the variants were Missense and belonged to the same chromatin-remodeling genes whose protein truncation variants are associated with severe neurodevelopmental syndromes. In the remaining cases, variants have been detected in genes with a role in cranial bone sutures, microcephaly, neural tube defects, and RASopathy. This study shows that the frequency of C1M is widely underestimated, in fact many of the variants, in particular those in the chromatin-remodeling genes, were inherited from a parent with C1M, either asymptomatic or with mild symptoms. In addition, C1M is a Mendelian trait, in most cases inherited as dominant. Finally, we demonstrate that modifications of the genes that regulate chromatin architecture can cause localized anatomical alterations, with symptoms of varying degrees.

Genetic counseling during COVID-19 pandemic: Tuscany experience.

BACKGROUND: COVID-19 outbreak prompted health centres to reorganize their clinical and surgical activity. In this paper, we show how medical genetics department's activity, in our tertiary pediatric hospital, has changed due to pandemic. METHODS: We stratified all our scheduled visits, from March 9th through April 30th, and assessed case-by-case which genetic consultations should be maintained as face-to-face visit, or postponed/switched to telemedicine. RESULTS: Out of 288 scheduled appointments, 60 were prenatal consultations and 228 were postnatal visits. We performed most of prenatal consultations as face-to-face visits, as women would have been present in the hospital to perform other procedures in addition to our consult. As for postnatal care, we suspended all outpatient first visits and opted for telemedicine for selected follow-up consultations: interestingly, 75% of our patients' parents revealed that they would have cancelled the appointment themselves for the fear to contract an infection. CONCLUSIONS: Spread of COVID-19 in Italy forced us to change our working habits. Given the necessity to optimize healthcare resources and minimize the risk of in-hospital infections, we experienced the benefits of telegenetics. Current pandemic made us familiar with telemedicine, laying the foundations for its application to deal with the increasing number of requests in clinical genetics.

Immunological Features of Neuroblastoma Amplified Sequence Deficiency: Report of the First Case Identified Through Newborn Screening for Primary Immunodeficiency and Review of the Literature.

This is the first case of NBAS disease detected by NBS for primary immunodeficiency. NBS with KRECs is revealing unknown potentialities detecting conditions that benefit from early recognition like NBAS deficiency. Immune phenotyping should be mandatory in patients with NBAS deficiency since they can exhibit severe immunodeficiency with hypogammaglobulinemia as the most frequent finding. Fever during infections is a known trigger of acute liver failure in this syndrome, so immune dysfunction, should never go unnoticed in NBAS deficiency in order to start adequate therapy and prophylaxis.