P 328. Novel Homozygous Variants Confirm SPTBN4-Related Congenital Myopathy and Expand the Clinical Phenotype

Background: Congenital myopathies are a group of rare Mendelian disorders characterized by hypotonia, hyporeflexia, and generalized weakness with clinical onset in early life. The molecular basis is heterogeneous, with disease-causing genes implicated in different cellular functions. Recently, one patient was reported with a homozygous variant in the SPTBN4 gene, encoding for βIV-spectrin, a nonerythrocytic member of the β-spectrin family. Here, we report two more families with three patients harboring novel homozygous variants of SPTBN4.

Aims: We sought to identify and describe new patients with a mutation in the SPTBN4 gene to further delineate the clinical phenotype of this novel disease and thereby establishing it as a clinical entity.

Hypothesis: The description of these new patients allows us to confirm that biallelic variants in the SPTBN4 gene can lead to a specific phenotype, characterized by myopathy und muscular hypotonia.

Methods: After whole exome sequencing (WES), bioinformatic filtering was applied and SPTBN4 identified as possible target. All clinical data available were used to describe the extend of the phenotype. Where possible, we performed immunohistochemistry for βIV-spectrin in muscle tissue.

Results: Family A: Two girls were born to healthy, first cousin parents from Saudi Arabia. Their phenotype largely resembles the first published case. They both suffered from neonatal onset hypotonia, soon feeding problems with aspiration became apparent. Motor development was delayed, and milestones such as head control, turning around the body axis, or crawling were never achieved. They do not suffer from central deafness. Genetic testing excluded known myopathy-associated mutations. Also, metabolic testing, electrodiagnostics, and imaging did not yield cues pointing toward an underlying syndrome. WES revealed the novel homozygous deletion (p.Asp1126fs) in SPTBN4 leading to a frameshift of the reading frame.

Family B: A girl was born to healthy second cousins on the paternal side. She carries a novel homozygous missense mutation (p.R246P) with a phenotype resembling in parts to the other patients. Overlapping features are muscle weakness, generalized hypotonia, poor head control, and feeding difficulties. Distinctively, she also suffers from nystagmus, hypersynchronic EEG activity, and choreoathetoid movements. Muscle histology showed signs of myopathy and type 2B fiber atrophy. Anti-βIV-spectrin staining is pending.

Discussion: The description of these novel patients allows us to confirm that biallelic variants in the SPTBN4 gene can lead to a specific phenotype, characterized by congenital myopathy, muscular hypotonia, absent muscular tendon reflexes, and feeding difficulties. Additional features such as nystagmus, EEG abnormalities, and movement disorder extend the clinical phenotype and possibly depend on the kind of mutation. The small number of patients identified does not allow for a genotype–phenotype correlation as of now. These novel cases show that SPTBN4 should be considered for genetic testing in patients with congenital myopathy.

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