A new case of SMABF2 diagnosed in stillbirth expands the prenatal presentation and mutational spectrum of ASCC1

Abstract

Spinal muscular atrophy with congenital bone fractures 2 (SMABF2) is a rare autosomal recessive neuromuscular disorder characterized by arthrogryposis multiplex congenita and prenatal fractures of the long bones, with poor prognosis. The most affected patients present with biallelic loss‐of‐function nucleotide variants in ASCC1 gene, coding a subunit of the transcriptional coactivator ASC‐1 complex, although the exact pathogenesis is yet unknown. This work describes the first case of SMABF2 in a stillbirth with documented evolution of the disease in the prenatal period. A microdeletion copy number variant (CNV) of about 64 Kb, involving four exons of ASCC1, was firstly detected by microarray analysis, requested for arthrogryposis and hydrops. Subsequent exome analysis disclosed a nucleotide variant of the same gene [c.1027C>T; (p. Arg343*)], resulting in the introduction of a premature termination codon. This stillbirth represents the first case of ASCC1 compound heterozygosity, due to an exonic microdeletion and a nucleotide variant, expanding the mutational spectrum of this gene. It also provides further evidence that exonic CNVs are an underestimated cause of disease‐alleles and that the integrated use of the last generation genetic analysis tools, together with careful clinical evaluations, are fundamental for the characterization of rare diseases even in the prenatal setting.

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.…”

Utility of fetal whole exome sequencing in the etiological evaluation and outcome of nonimmune hydrops fetalis

“…SMABF2 is characterized by intrauterine onset of fetal hypotonia and hypokinesia resulting in arthrogryposis multiplex along with intrauterine fracture of long bones. To date, only six families with SMABF2 have been reported in the literature, with NIHF reported as a presenting feature in a single case 38 . The fetus in the present study harbored two protein truncating variants –p.Arg138Ter, a known variant reported in a patient from Sri Lanka, 31 and p.Phe155SerfsTer15, a novel variant.…”