CONGENITAL MUSCULAR DYSTROPHIES: P.334Recessive loss-of-function mutations in ITGA7 cause cardiac arrhythmia with or without structural cardiomyopathy and respiratory muscle weakness

Abstract

Integrin α7 encoded by ITGA7 is highly expressed in skeletal and cardiac muscle and contributes to sarcolemmal stability by binding to laminin α2. Three unrelated patients were previously reported with ITGA7-linked congenital muscular dystrophy. Here, we report three patients from two unrelated families presenting with adult-onset cardiac arrhythmia and respiratory weakness due to recessive null mutations in ITGA7. Patient I, a 51-year-old male presented with delayed motor milestones, stridor since birth, cardiac arrhythmia (frequent ventricular ectopy, non-sustained ventricular tachycardia and premature conduction disease) requiring ICD at 46 years. Cardiac MRI showed basal septal hypertrophy and fibrosis. Examination showed focal wasting of medial gastrocnemii and respiratory impairment. EMG was myopathic. Two other male siblings also reported cardiac symptoms. Patient IIa, a 61-year-old female presented at 49 years with febrile respiratory distress requiring mechanical ventilation and tracheostomy. She had a history of atrial flutter, left bundle branch block and atrioventricular block requiring a pacemaker. She presented with further episodes of relapsing respiratory insufficiency. Examination showed mild weakness of ankle dorsiflexion (MRC 4+) and vocal cord paresis. EMG was myopathic. Muscle ultrasound showed widespread hyperechogenicity in the limb muscles. Patient IIb, her female sibling aged 55 presented with chronic hypoventilation. She had mild limb weakness. Presently she uses nocturnal non-invasive ventilation. Quadriceps biopsies (PI and PIIa) revealed non-specific myopathic changes. Next generation sequencing revealed a homozygous c.806_818del [p.S269fs] variant (PI) and two canonical splice site variants (PIIa, PIIb), (c.2357+1G>A [r.spl?] and c.2278-1G>A [r.spl?]) in ITGA7. Immunostaining revealed absent sarcolemmal integrin α7 labeling in both biopsies. Evaluation of α7-integrin-null mice showed a mild progressive myopathy with mainly diaphragmatic involvement and similar pathological features. Patients with predominant respiratory weakness and/or cardiac arrhythmias with or without structural cardiomyopathy should be screened for mutations in ITGA7.