Myopathy With SQSTM1 and TIA1 Variants: Clinical and Pathological Features

Zhiyv Niu, Carly Sabine Pontifex, Sarah Berini, Leslie E. Hamilton, Elie Naddaf, Eric Wieben, Ross A. Aleff, Kristina Martens, Angela Gruber, Andrew G. Engel, Gerald Pfeffer, Margherita Milone

The aim of this study is to identify the molecular defect of three unrelated individuals with late-onset predominant distal myopathy; to describe the spectrum of phenotype resulting from the contributing role of two variants in genes located on two different chromosomes; and to highlight the underappreciated complex forms of genetic myopathies. Clinical and laboratory data of three unrelated probands with predominantly distal weakness manifesting in the sixth-seventh decade of life, and available affected and unaffected family members were reviewed. Next-generation sequencing panel, whole exome sequencing, and targeted analyses of family members were performed to elucidate the genetic etiology of the myopathy. Genetic analyses detected two contributing variants located on different chromosomes in three unrelated probands: a heterozygous pathogenic mutation inSQSTM1(c.1175C>T, p.Pro392Leu) and a heterozygous variant inTIA1(c.1070A>G, p.Asn357Ser). The affected fraternal twin of one proband also carries both variants, while the unaffected family members harbor one or none. Two unrelated probands (family 1, II.3, and family 3, II.1) have a distal myopathy with rimmed vacuoles that manifested with index extensor weakness; the other proband (family 2, I.1) has myofibrillar myopathy manifesting with hypercapnic respiratory insufficiency and distal weakness. The findings indicate that all the affected individuals have a myopathy associated with both variants inSQSTM1andTIA1, respectively, suggesting that the two variants determine the phenotype and likely functionally interact. We speculate that theTIA1variant is a modifier of theSQSTM1mutation. We identify the combination ofSQSTM1andTIA1variants as a novel genetic defect associated with myofibrillar myopathy and suggest to consider sequencing both genes in the molecular investigation of myopathy with rimmed vacuoles and myofibrillar myopathy although additional studies are needed to investigate the digenic nature of the disease.