Spinal muscular atrophy with congenital bone fractures 2 caused by a rare loss‐of‐function ASCC1 gene mutation in two Bulgarian Roma patients

The last 25 years have been the Golden age of Genetics, with the disease genes responsible for many genetic neuromuscular disorders now identified. The clinical implementation of genomic medicine results in rapid expansion of knowledge regarding genetic basis and pathophysiology of rare and previously unknown conditions. Here we present two unrelated newborns of Roma origin deceased at early infant age with clinical presentation of congenital muscular weakness, respiratory distress, multiple congenital contractures, and long bone fractures. Written informed consent and blood samples were obtained from both couples. Patient 1 was a male newborn from the first pregnancy of consanguineous parents of Roma descent delivered via cesarean section with normal growth parameters at birth. The child was cyanotic, hypothermic, and hypotonic, with areflexia, multiple joint contractures, fractures of femur and humerus, bilateral cryptorchidism. He developed progressive respiratory failure necessitating mechanical ventilation and died 12 days past birth. Osteogenesis imperfecta was suspected initially. Post mortem NGS (TruSight One, Illumina) and Sanger sequencing of DNA extracted from umbilical cord detected a homozygous loss-of-function donor splice-site mutation c.626+1G>A in ASCC1 gene associated with Spinal muscular atrophy with congenital bone fractures-2 (SMABF2) (OMIM 616867)—a severe autosomal recessive neuromuscular condition, characterized by prenatal-onset spinal muscular atrophy, arthrogryposis multiplex congenita (AMC), respiratory distress, and congenital bone fractures. The substitution NM_001198800.3:c.626+1G>A (NM_001198799.3:c.710+1G>A,rs747595523), destroys donor splicesite of exon 7/ intron 7 boundary of the ASCC1 gene and is expected to disrupt mRNA maturation with no ASCC1 protein synthesis. The reported global allele frequency is 0.0000131 (gnomAd). The segregation analysis confirmed the presence of heterozygous variant in both parents. Retrospectively the patient was diagnosed with SMABF2. Genetic counseling of the family and prenatal diagnosis of the next pregnancy was performed and a healthy noncarriermalewas delivered.