ASCC1 – Spinal Muscular Atrophy with Congenital Bone Fractures 2

ASCC1 encodes a subunit of the ASC-1 transcriptional coactivator complex and is implicated in spinal muscular atrophy with congenital bone fractures 2 (SMABF2), an ultrarare autosomal recessive neuromuscular and bone fragility disorder. Clinically, SMABF2 presents with prenatal‐onset hypotonia, arthrogryposis multiplex congenita, long‐bone fractures, and perinatal lethality. Pathogenicity arises from biallelic loss‐of‐function variants, including nucleotide substitutions introducing premature stop codons and multi‐exon deletions.

Genetic evidence comprises six unrelated probands: a stillbirth with compound heterozygosity for a 64 Kb exon deletion and c.1027C>T (p.Arg343Ter) ([PMID:31880396]); a pediatric case with c.395-2A>G splice alteration and two-exon deletion ([PMID:35838082]); three infants each harboring homozygous nonsense or frameshift alleles ([PMID:30327447]); and one infant with a homozygous deletion identified via exome sequencing ([PMID:37455927]). All variants segregate in trans in parental carriers, confirming autosomal recessive inheritance.

The variant spectrum is dominated by protein‐truncating alleles: multiple nonsense (e.g., c.1027C>T (p.Arg343Ter), c.812G>A (p.Trp271Ter)), frameshift (e.g., c.157dup (p.Glu53fs)), splice‐site (c.872-1G>C, c.395-2A>G), deep‐intronic insertions, and multi‐exon deletions. No recurrent or founder variants have been described to date.

Functional studies corroborate pathogenicity: muscle biopsies reveal sarcolemmal oxidative rims and Z-band abnormalities ([PMID:30327447]), while patient fibroblasts show absent ASCC1 expression, downregulation of osteogenic regulators RUNX2 and SERPINF1, and impaired TGF-β/SMAD signaling ([PMID:37455927]). ASCC1 knockdown in hMSCs shifts differentiation away from osteoblasts toward adipocytes with reduced mineralization, supporting a loss‐of‐function mechanism.

No studies have refuted the association; all experimental and clinical data consistently demonstrate that ASCC1 deficiency underlies SMABF2. Additional evidence from high-resolution structural analyses strengthens understanding of ASCC1’s RNA‐binding and enzymatic domains but exceeds current ClinGen scoring.

Key Take-home: Bi-allelic truncating variants in ASCC1 cause autosomal recessive SMABF2 with prenatal muscle and bone defects; genetic testing for loss‐of‐function alleles in ASCC1 is recommended for diagnostic confirmation.

References

• American journal of medical genetics. Part A • 2020 • A new case of SMABF2 diagnosed in stillbirth expands the prenatal presentation and mutational spectrum of ASCC1. PMID:31880396
• American journal of medical genetics. Part A • 2022 • Congenital myopathy as a new phenotype caused by two undescribed variants in ASCC1 gene. PMID:35838082
• Journal of medical genetics • 2019 • Novel ASCC1 mutations causing prenatal-onset muscle weakness with arthrogryposis and congenital bone fractures. PMID:30327447
• Frontiers in endocrinology • 2023 • Investigating the role of ASCC1 in the causation of bone fragility. PMID:37455927
• The Journal of biological chemistry • 2024 • ASCC1 structures and bioinformatics reveal a novel helix-clasp-helix RNA-binding motif linked to a two-histidine phosphodiesterase. PMID:38750793

Evidence Based Scoring (AI generated)