Recessive TTN mutations: Escobar syndrome, arthrogryposis, and congenital heart defect in Brazilian patients

Background: The TTN gene is related to a broad phenotype spectrum including tibial muscular dystrophy, hereditary myopathy with respiratory failure, limb girdle dystrophy 2J and dilated or hypertrophic cardiomyopathy. In 2014, Chauveau et al, described phenotypes including cardiac septal defects, left ventricular non-compaction, Emery-Dreifuss dystrophy and arthrogryposis. In 2020, Savarese et al, showed most of patients with biallelic TTN mutations presented as congenital myopathy.

Objective: We describe 4 patients with TTN mutations and different phenotypes: one presenting as Escobar syndrome, one with arthrogryposis and cardiac septal defects and two with multiple arthrogryposis, short neck and scoliosis.

Methods: Patients were clinically evaluated, and the molecular study was done using whole exome sequencing (WES).

Results: A 7-year-old-boy, second child from non-consanguineous parents. He presented multiple pterigia, short stature, scoliosis, bilateral ptosis, muscle weakness and ventilation failure, requiring the use of non-invasive assisted ventilation since he was 3 years old. The muscle biopsy showed myopathic pattern. A diagnosis of Escobar Syndrome was made, and molecular study showed two TTN truncating mutations: c.669+1G>A and c.54769delT Case 2: A 14-month-old-girl, child of a non-consanguineous parents. At six months of age, she presented a motor delay, hypotonia, global muscle weakness and arthrogryposis. The Echocardiogram showed left ventricular non-compaction and ventricular septum defects. WES showed two truncating mutations: c. 101608+1 G>A was paternally inherited and the c. 46658G>A which was de novo and a novel mutation. Case 3: A 3-year-old-girl, child of a non-consanguineous parents, presenting multiple arthrogryposis, short neck and scoliosis, cervical pterygia, myopathy and severe scoliosis. WES showed two TTN mutations: c.56648-1G>A e c.19744C>T. Case 4: A 10-year-old-boy, child of a non-consanguineous parents, presented multiple arthrogryposis, short neck and scoliosis, myopathy and severe scoliosis. At 7 years of age, was necessary to start with noninvasive ventilation. WES showed two TTN mutationsc.669+1G>A p. and c.18920delG p. Ser6307Ilefs*17.

Conclusions: The TTN gene is associated to a phenotype spectrum. In the present report, the recessive TTN mutations are related to congenital myopathy, arthrogryposis plus congenital heart defects and to the phenotype of Escobar Syndrome. It is very important to have the genetic diagnosis which allows the genetic counseling.

 

MissingLinkText

No conflict of interest has been declared by the author(s).

Publication History

Article published online:
18 September 2023