The constantly evolving spectrum of phenotypes in titinopathies – will it ever stop?

Abstract

Purpose of review The last few years have confirmed previous assumptions of an enormous impact of the titin gene (TTN) on the occurrence of muscle disease, cardiomyopathy, or both together. The reason for this rather late understanding of its importance is because of the huge size which prevented sequencing of the whole gene by the previous Sanger technique in the individual cases. An update of the advances in diagnosing titinopathies is the main focus of this review. Recent findings High throughput methods are now widely available for TTN sequencing and a corresponding explosion of different types of identified titinopathies is observed and published in the literature, although final confirmation is lacking in many cases with recessive missense variants. Summary The implications of these findings for clinical practice are easy to understand: patients with previously undiagnosed muscle disease can now have a correct diagnosis and subsequently receive a likely prognosis, can have accurate genetic counseling for the whole family and early treatment for predictable complications from the heart and respiratory muscles. In addition not to forget, they can avoid wrong diagnoses leading to wrong treatments.

Centronuclear myopathy due to a de novo nonsense variant and a maternally inherited splice‐site variant in TTN: A case report

“…Genotypes of recessive titin‐related myopathies are more complicated. Biallelic deleterious truncating mutations such as nonsense and frameshift variants with proven segregation in trans were considered pathogenic 3 . The interpretation of splicing variants should be careful, even the variant is in the canonical splice sites.…”

“…The interpretation of splicing variants should be careful, even the variant is in the canonical splice sites. Downstream effect of splicing variants on the messenger RNA (mRNA) and protein level should be carefully evaluated when possible 3,12,14,18 . While the interpretation of missense variants is tricky because the current bioinformatics tools cannot predict their functional impact effectively, and only very few missense variants have been confirmed as pathogenic 11,20,21 .…”

“…With its 363 coding exons and a full‐length transcript of more than 100 kb, TTN (MIM#188840) encodes the largest polypeptide in nature named titin, which is an essential component of the sarcomere, spanning half the sarcomere from the Z‐disk to the M‐line. 1 , 2 , 3 TTN mutations have been reported to cause a wide spectrum of cardiomyopathy, skeletal muscle diseases, or both together. 3 The spectrum of TTN mutations varies in terms of mode of inheritance (dominant versus recessive) and location of variants.…”

“… 1 , 2 , 3 TTN mutations have been reported to cause a wide spectrum of cardiomyopathy, skeletal muscle diseases, or both together. 3 The spectrum of TTN mutations varies in terms of mode of inheritance (dominant versus recessive) and location of variants. Heterozygous truncating TTN mutations have been recognized as the most common genetic cause of dilated cardiomyopathy (DCM), which are predominantly found in the A‐band region of titin.…”

“… 5 , 6 Recessive TTN mutations cause a wide range of muscle disease with or without cardiomyopathy which have been reported under different terms in the past, such as recessive early‐onset myopathy with fatal cardiomyopathy, centronuclear myopathy (CNM), core myopathy with heart disease, and arthrogryposis multiplex congenita with myopathy and others. 3 , 7 , 8 , 9 , 10 , 11 , 12 …”