Angelo Selicorni

Tra le tante forme con ipotonia, non dimenticarti la faccetta mia

Neurodevelopmental disorders (NDDs) are often the results of genetic factors, whose identification and key role in their etiology may be elusive. Despite advancements in genetic testing, many cases remain unsolved. Single-nucleotide variants in a critical 18-bp region of the noncoding gene RNU4-2, a crucial component of the spliceosome complex, have been recently recognized as being responsible for ReNU syndrome, also known as NDD with hypotonia, brain anomalies, distinctive facies, and absent language (NEDHAFA). The aim of this study was to investigate the prevalence of RNU4-2 variants within a cohort of unsolved patients exhibiting NDDs from the Telethon Undiagnosed Disease Program (TUDP). We conducted a reanalysis of genomic data using bioinformatic tools, followed by direct sequencing to identify variants in the RNU4-2 critical region. Causative variants were detected in 11 of 375 tested individuals, allowing us to diagnose 2.93% of our unsolved cohort. All heterozygous variants in RNU4-2 occurred de novo, including 10 with the recurrent n.64_65insT insertion and 1 with n.77_78insT. Structural modeling suggested that these variants disrupt the U4/U6 snRNA interaction, potentially impairing spliceosome function. Our findings reinforce the critical role of RNU4-2 variants in syndromic NDDs and underscore the importance of noncoding regions in genetic diagnoses. These findings show that RNU4-2 variants account for approximately 2.9% of the patients with TUDP in this study and highlight the need for integrating advanced molecular techniques and data sharing to refine diagnoses and enhance our understanding of rare genetic disorders.

TSPEAR (chr. 21q22.3) encodes a protein involved in tooth development and is predominantly expressed in the enamel knot. Biallelic loss of function variants in TSPEAR cause ectodermal dysplasia, tooth agenesis and sensorineural hearing loss. However, the role of TSPEAR in auditory processes is unclear. This study aimed at better delineating the allelic and clinical spectrum of TSPEAR ‐associated disorders. We identified homozygous and compound heterozygous causative variants in TSPEAR [NM_144991.3] in 11 patients from seven families. Abnormalities in tooth number and shape (conical teeth and tooth agenesis with a variable number of missing teeth) were found in all affected individuals. Maxillary retrusion was present in 6/11. Manifestations in other ectodermal‐derived organs were seen in a minority of patients. None of the individuals had hearing loss. We identified a total of 10 variants, of which seven have not been previously published, and analyzed the effect of missense variants to support their pathogenicity. Our results demonstrate that individuals with biallelic variants in TSPEAR show complete penetrance for dental manifestations, but not for other ectodermal abnormalities. TSPEAR ‐related disorder is more common than previously thought, while hearing loss is not a feature of the disease.

Facies suggestiva, ritardo psicomotorio/disabilità intellettiva, anomalie ectodermiche, possibili cardiopatie congenite, ipoplasia/aplasia della quinta falange distale

E hai un’anomalia di esofago e ano, guarda bene rene, arti e vertebre pensando all’associazione VATER

The cohesin complex plays crucial roles in DNA repair, chromatid separation, and gene transcription regulation. Pathogenic variants in cohesins or dysfunctional transcriptional regulators lead to cohesinopathies, a broader group of disorders including Cornelia de Lange Spectrum (CdLSp), for which the prevalence of cancer cases remains unclear. Here, we aimed to assess the prevalence of oncological events in CdLSp and elucidate the role of cohesin variants in cancer predisposition. We developed a custom next‐generation sequencing (NGS) panel targeting predisposition and pathogenic genes, which we applied on N = 120 samples of pediatric patients with acute lymphoblastic leukemia (ALL), identifying 11 out of 229 total—10 germline and 1 somatic—variants in cohesin genes. Data of N = 205 brain tumors were extracted by bioinformatic analysis of data from open‐source databases carrying 19 somatic variants. In a cohort of 54 CdLSp patients, the largest cohort from a single center, with a median age of 13 years, the hypothesis of an increased prevalence of cancer in CdLSp was not confirmed. Our findings highlight a significant involvement of germline NIPBL variants in CdLSp, whereas RAD21 and STAG1/2 are predominantly found as somatic variants in neoplasms. However, a distinct genetic or molecular pattern distinguishing variants leading to CdLSp from tumors was not identified. Hence, we advocate for further investigation into the relationship between cohesin variants and cancer predisposition in a larger cohort of patients, with a longer observation time and including different types of malignancies, with more focus on epigenetic approaches.

Se oltre al ritardo c’è la (alfa) talassemia, per la diagnosi non serve troppa fantasia

Qualche dito e qualche chilo in più, con una vista, uno sviluppo e una funzione renale compromesse