Novel compound heterozygous pathogenic variants in ASCC1 in a Chinese patient with spinal muscular atrophy with congenital bone fractures 2 : evidence supporting a "Definitive" gene-disease relationship

Abstract

Background: A very limited spectrum of ASCC1 pathogenic variants had been reported in five (mostly consanguineous) families with spinal muscular atrophy with congenital bone fractures 2 [OMIM #616867] since 2016. Methods:A proband from a non-consanguineous Chinese family presented with neonatal severe hypotonia, respiratory distress, muscle weakness and atrophy, as well as congenital bone fractures was examined by exome sequencing. Results: A compound heterozygosity of a nonsense (c.932C>G ,p.Ser311Ter) and an exon 5 deletion in ASCC1 segregating with phenotypes was detected, both variants are novel and pathogenic. Since ASCC1 is a relative new disease gene, we performed the gene curation following ClinGen SOP. The existing evidence is sufficient to support a "Definitive" level of disease-gene relationship. Conclusion: This case report expended the mutation spectrum of ASCC1 and support the notion that this novel disease also occur in outbreed populations and this is a rare disease but may still be underdiagnosed due to its perinatal lethal outcomes. Keywords: spinal muscular atrophy with congenital bone fractures 2; ASCC1 ; compound heterozygous; gene curation; exome sequencing

Biallelic ASCC1 variants including a novel intronic variant result in expanded phenotypic spectrum of spinal muscular atrophy with congenital bone fractures 2 (SMABF2)

“…Our proband was found to have biallelic variants in ASCC1 and her clinical phenotype is consistent with SMABF2 as reported in 11 other infants (Table 1). (Bohm et al, 2019; Giuffrida et al, 2020; Knierim et al, 2016; Lu et al, 2020; Oliveira et al, 2017) The findings in our proband confirm the association of biallelic variants in ASCC1 with SMABF2 characterized by severe diffuse hypotonia and congenital fractures and extends the phenotypic spectrum with her unique features of cleft palate, small spleen, transverse liver, cardiac abnormalities, and pulmonary vasculature with thromboemboli with chondroid appearance. The muscle histology findings of fiber atrophy, myofibrillar disorganization, and enlarged Z‐bands are typical for SMABF2.…”

“…Biallelic variants in ASCC1 (MIM# 616867) have been recently identified as the underlying cause of a rare form of AMC known as spinal muscular atrophy with congenital bone fractures 2 (SMABF2) (Bamshad et al, 2009; Giuffrida et al, 2020; Knierim et al, 2016; Lu et al, 2020; Oliveira et al, 2017). ASCC1 encodes a subunit of the tetrameric ASC‐1 transcriptional co‐integrator complex that includes ASCC1, ASCC2, ASCC3, and TRIP4 (Jung et al, 2002).…”

Inherited Defects of the ASC-1 Complex in Congenital Neuromuscular Diseases

“…The question of primary motor neuron versus muscle involvement has not been clarified by more recent reports of three other patients with 5 novel ASCC1 mutations. Their clinical presentation was consistent with the lethal perinatal phenotype described above, including congenital bone fractures [ 33 , 34 , 35 ], mild brain ventricle dilatation abnormalities in one patient [ 35 ] and one stillbirth [ 24 ]. The muscle biopsy from one of them was reported as atrophic with no further description [ 33 ] and no muscle biopsies were performed in the remaining two cases.…”

“…Congenital bone fractures, present in only two families with TRIP4 mutations [ 23 ], are part of the clinical phenotype in all the ASCC1 -mutated patients [ 24 , 33 , 34 , 35 ]. Although prenatal fractures have been non-specifically reported in other forms of congenital muscle disease [ 54 , 55 , 56 ], their frequency in ASCC1 -mutant cases suggests that, in this context, they are not an unspecific consequence of fetal immobility but directly linked to a role of ASCC1 in bone.…”

“…The muscle biopsy from one of them was reported as atrophic with no further description [ 33 ] and no muscle biopsies were performed in the remaining two cases. Dysmorphic features and a myopathic appearance were observed in most of these cases [ 33 , 35 ]. Although some of these patients were labeled as having SMA by analogy with the first cases with ASCC1 mutations reported, no electrophysiological study or in-depth histopathological examination was performed supporting or clarifying this diagnosis.…”