ZNF711 is one of eleven zinc-finger genes on the X chromosome that have been associated with X-linked intellectual disability. This association is confirmed by the clinical findings in 20 new cases in addition to 11 cases previously reported. No consistent growth aberrations, craniofacial dysmorphology, malformations or neurologic findings are associated with alterations in ZNF711. The intellectual disability is typically mild and coexisting autism occurs in half of the cases. Carrier females show no manifestations. A ZNF711-specific methylation signature has been identified which can assist in identifying new cases and in confirming the pathogenicity of variants in the gene.
Optimal lysosomal function is essential for early tissue development. This is evidenced by the large number of inherited disorders, collectively called the lysosomal storage disorders (LSDs), caused by lysosomal dysfunction. Although it is clear that macromolecular accumulation adversely impacts tissue development, the breadth of downstream pathways contributing to pathology has yet to be elucidated. Multiple studies indicate that mechanisms beyond lysosomal storage also profoundly influence early tissue formation. Of these, abnormal growth factor signaling has been linked to pathology in several different LSDs. Recent work in a zebrafish model of sialidosis demonstrated that mislocalizing lysosomal cathepsins by increased exocytosis disrupts the TGFβ-related signaling pathways that control skeletal formation. Here, we show that loss of N-acetyl galactosamine-6-sulfatase (galns) also enhances lysosomal exocytosis in developing cartilage of mutant zebrafish. Unlike in sialidosis, however, in galns mutants, increased exocytosis was associated with reduced cathepsin activity, lower levels of TGFβ and BMP signaling, and altered abundance of intracellular and extracellular glycosaminoglycans. Together, these data highlight a role for lysosomal exocytosis and protease-mediated alterations in growth factor signaling in the onset of mucopolysaccharidosis type IVA skeletal pathology.
PURPOSE:The ERBB4 gene encodes a tyrosine kinase receptor for neuregulins and EGF family members, and plays a crucial role in various neurobiological processes. At present, the phenotypic manifestations of genetic variants that disrupt ERBB4 gene function (null variants) are not well established. METHODS:A search for new patients with null variants in ERBB4 was initiated through an international data-sharing collaboration via GeneMatcher, and by searching the databases Decipher and ClinVar. Diagnosis had been performed using chromosomal microarray analysis, whole-exome sequencing, or whole-genome sequencing. RESULTS:Twenty-four new patients from 13 unrelated families with null variants in ERBB4 were identified. Genetic findings included single- or multiple-exon deletions in eight families, a reciprocal translocation disrupting ERBB4 in one family, and sequence variants in four. Variants arose de novo in four probands, were inherited in eight, and had an unknown inheritance pattern in one. Co-segregation of variants with clinical manifestations was observed within families. The predominant clinical features included neurodevelopmental disorders (intellectual disability, neurodevelopmental delay, autism spectrum disorder, and attention deficit hyperactivity disorder), speech delay, challenging behaviors, hypotonia, psychiatric conditions and seizures. CONCLUSION:This study represents the largest case series of patients with neurological disorders and null variants in the ERBB4 gene. Our findings support haploinsufficiency as the most plausible pathophysiological mechanism underlying ERBB4-related disorders and broaden the spectrum of associated phenotypes. Autism spectrum disorders and psychiatric manifestations have emerged as frequent, previously underrecognized features. Penetrance appears to be high but incomplete, and expressivity is highly variable, with a tendency toward intrafamilial phenotypic conservation.
Recent studies have described acquired ring chromosomes (aRCs), marker chromosomes, and extrachromosomal DNA (ecDNA) in various tumors. However, the genomic copy number aberrations (CNAs) and gene rearrangements within these aRCs require further genomic analysis, and the knowledge base to interpret their clinical implications remains largely unformed. A working group was organized by the International Consortium of Human Ring Chromosomes (ICHRC) to conduct a systematic evidence review of the role of aRCs in hematologic malignancies. This retrospective review summarizes the current molecular cytogenetic and genomic technologies for aRC analysis, presents an overview of the types of aRCs in various hematological malignancies, and provides evidence to support cytogenomic analysis and diagnostic interpretation. The findings from this study recommend an integrated cytogenomic analysis for aRCs and prompt further functional analyses to elucidate the molecular mechanisms for disease causation and targeted treatment.
Spliceosomopathies are syndromes caused by pathogenic variants in genes involved in splicing and mRNA metabolism. Here, we report a novel spliceosomopathy caused by de novo variants in SF3B3, encoding a subunit of the spliceosomal SF3b complex. We performed genomic, clinical, computer-aided gestalt analysis, molecular dynamics simulations, and functional studies using patient-derived fibroblasts. Through international data sharing, we collected clinical and molecular data from 24 unrelated individuals with heterozygous SF3B3 variants, mostly missense, consistent with autosomal dominant inheritance. Individuals exhibited a congruent phenotype including autism spectrum disorder (ASD), developmental delay (DD), intellectual disability (ID), language and motor delay, multiple congenital anomalies, and distinctive craniofacial features, confirmed by GestaltMatcher analysis. In patient fibroblasts, SF3B3 mRNA was within the normal range, whereas protein levels were reduced by approximately 15–30
