Novel Variants of ANO5 in Two Patients With Limb Girdle Muscular Dystrophy: Case Report

Abstract

Here we report on two unrelated adult patients presenting with Limb girdle muscular dystrophy who were found to have novel variants in ANO5. Both patients had prominent weakness of their proximal lower limbs with mild weakness of elbow flexion and markedly elevated creatine kinase. Next generation sequencing using a custom-designed neuromuscular panel was performed in both patients. In one patient, 336 genes were targeted for casual variants and in the other patient (using a later panel design), 464 genes were targeted. One patient was homozygous for a novel splice variant [c.294+5G>A; p.(Ala98Ins4^*)] in ANO5. Another patient was compound heterozygous for two variants in ANO5; a common frameshift variant [c.191dupA; p.(Asn64fs)] and a novel missense variant [c.952G>C; p.(Ala318Pro)]. These findings support the utility of next generation sequencing in the diagnosis of patients presenting with a Limb girdle muscular dystrophy phenotype and extends the genotypic spectrum of ANO5 disease.

Keywords: ANO5; case report; limb girdle muscular dystrophy; next generation sequencing; novel variant.

Figure 1

Magnetic resonance imaging (MRI) of selected muscles from patients 1 and 2. (A) Left shoulder of patient 1 - axial T2* weighted sequence showing increased T2 signal of teres major and long head triceps (white arrows). (B) Bilateral thighs of patient 2 - coronal T1^∧ weighted sequence showing extensive fatty replacement of anterior and medial thigh muscles (white arrows) with relative preservation of the right rectus femoris (black arrow). *T2, transverse relaxation time; ^∧T1, longitudinal relaxation time.

Figure 2

DNA sequence chromatogram for patient 1. (A) Normal control mRNA. (B) Patient 1 mRNA showing loss of exon 5 donor splice site resulting in intron inclusion and premature termination of protein due to presence of stop codon in variant mRNA.