Summary: One of the seminal discoveries from genetic studies of autism spectrum disorder and related neurodevelopmental disorders (NDDs) has been that loss-of-function (LoF) mutations in genes that impact transcriptional regulation confer substantial liability to NDDs. Haploinsufficiency of the epigenetic regulator POGZ represents one of the strongest such associations; however, little is known about the mechanisms by which POGZ LoF alters early neuronal development. Here, we created an allelic series of CRISPR-engineered human induced pluripotent stem cell (hiPSC) clones harboring mono- and bi-allelic POGZ deletions. In hiPSC-derived neural stem cells (NSCs) and Neurogenin-2-induced neurons (iNs), POGZ LoF altered the expression of genes associated with synaptic and intracellular signaling and extracellular matrix organization. Our multiomics profiling also showed altered footprinting of critical transcription factors (e.g., activator protein 1 complexes) that were enriched at promoters of differentially expressed genes associated with synaptic function. To further interrogate the shared molecular changes associated with NDDs, we compared our results to deletions of the transcription factor MEF2C and the sodium channel gene SCN2A that we generated in these same isogenic iNs. These analyses revealed strong enrichment of extracellular matrix and intracellular signaling disruption associated with POGZ and MEF2C deletion, whereas POGZ and SCN2A haploinsufficiency exhibited shared transcriptional effects on gene modules enriched for NDD-associated genes with opposing regulatory effects. Notably, we also observed alterations to synaptic firing rate and neurite extension with bi-allelic deletions. These shared molecular consequences suggest key points of convergence that connect gene regulation to neuronal function in the etiology of neurodevelopmental pathologies.
Summary: TUBB2B encodes a β-tubulin isotype essential for neuronal proliferation, migration, and organization during brain development. Pathogenic heterozygous variants in TUBB2B are associated with neurodevelopmental disorders including polymicrogyria and corpus callosum abnormalities. However, the phenotypic spectrum remains heterogeneous, most likely reflecting variant-specific effects on microtubule formation and stability. Homozygous TUBB2B variants are exceedingly rare, with one family reported to date. We describe five individuals in four families with rare TUBB2B variants. Four variants are described, including a previously reported de novo missense variant, c.292G>A (GenBank: NM_178012.5 ) (p.Gly98Arg), with potential phenotypic expansion including panhypopituitarism; a previously reported de novo missense variant, c.605T>C (GenBank: NM_178012.5 ) (p.Ile202Thr), showing interindividual heterogeneity; a de novo missense variant, c.43C>A (GenBank: NM_178012.5 ) (p.Gln15Lys) at a polyamination site critical for microtubule stability; and a homozygous missense variant within a region of absence of heterozygosity in two siblings from consanguineous parents, c.145G>A (GenBank: NM_178012.5 ) (p.Val49Ile). Both individuals also carry a pathogenic homozygous truncating ALKBH8 variant c.1675del (GenBank: NM_138775.3 ) (p.Arg559Alafs∗56), representing a potential dual molecular diagnosis driving clinical features reflective of contributions from both genes. These reports expand the clinical spectrum of TUBB2B -related tubulinopathies, illustrate phenotypic heterogeneity, and provide insights into disease mechanisms including effects at polyamination sites and rare recessive inheritance, underscoring the need for nuanced genotype-phenotype interpretation in diagnostic and counseling contexts.
Summary: Activating Signal Cointegrator 1 Complex, Subunit 3 ( ASCC3 ) encodes a DNA helicase that is pivotal in transcriptional regulation, DNA damage response, and ribosomal quality control. Bi-allelic ASCC3 variants have been recently associated with a wide spectrum of non-lethal neuromuscular and neurodevelopmental disorders, with no consistent brain malformations or endocrine dysfunction. We describe a severe lethal form of ASCC3 disease: eight individuals of three consanguineous Bedouin families presented with a consistent phenotype of severe global developmental delay, axial hypotonia, and hypoplasia of the corpus callosum, lethal in infancy. Shared dysmorphic features included narrow palpebral fissures, a sunken flat nasal bridge with a short nasal tip and anteverted nares, and low-set ears. Congenital hypothyroidism was evident in most affected individuals, and all males had micropenis/cryptorchidism. Linkage analysis identified a chromosome 6q16.3 locus segregating within the families consistent with autosomal recessive inheritance (maximum multipoint LOD score: 3.1). Whole-exome sequencing followed by segregation analysis identified within this locus a single disease-associated variant: ASCC3 c.3061T>A (GenBank: NM_006828.4 ) (p.Phe1021Ile). The phenotype, consistent across all affected individuals, significantly broadens the phenotypic spectrum of ASCC3 -related disorders, with unique dysmorphism, previously unreported agenesis of the corpus callosum, micropenis/cryptorchidism, congenital hypothyroidism (possibly relevant to ASCC3’s pituitary and thyroid expression and its thyroid hormone receptor interacting protein 4 [TRIP4] interaction), and early lethality.
Summary: Hepatocellular carcinoma (HCC) is the third leading cause of cancer death globally, often arising on a background of cirrhosis. Here, we aimed to establish genetic drivers of all-cause HCC across ancestries in a large meta-analysis. We included 15 cohorts comprising 17,697 HCC affected individuals and 2,715,683 control subjects in this meta-analysis. We found 15 genome-wide significant ( p < 5 × 10 −8 ) germline loci, including in/near GCKR , MTTP , ADH5 , 8q24.21 (nearest gene MYC ), MAP3K9 , and GABPB2 , and a further two loci found on transcriptome- and regulome-wide association analyses. MAP3K9 , TERT , and GABPB2 variants act independently of cirrhosis on both colocalization analysis and sensitivity analyses. There was significant ancestral heterogeneity in six loci including variants in the HLA locus that had divergent effects on HCC risk between East Asian and European ancestries. Fine mapping identified 11 potentially causal coding variants, including p.Leu446Pro (c.1337T>C) in GCKR and p.Asp423Glu (c.1269C>T) in MEN1. MEN1 , 8q24.21 (nearest gene MYC ), and TERT are all involved in the β-catenin pathway transactivation complex. Transcriptome-wide analysis identified enrichment of germline-encoded DHRS1 in HCC. Regulome-wide analysis replicated the germline signal for EPHA2 and found a chromatin-accessible region containing genes ZNF367 and HABP4 . Finally, we demonstrated that population-level genetic architecture for HCC overlaps with steatotic and viral liver disease, and individuals with genetic risk for lower body mass index have higher risk of HCC. Genetic risk for HCC is determined by germline susceptibility to β-catenin pathway activation and cirrhosis. HCC is driven by both heterogeneous and homogeneous genetic factors across ancestries.
