Homozygote Deletion of Fukutin Gene (FKTN) Exon 3 Causes Dilated Cardiomyopathy and Mild Limb-Girdle Muscular Dystrophy without Brain Involvement

Background: FKTN mutations (MIM607440) cause three different forms of muscular dystrophy-dystroglycanopathy: a severe congenital form with brain and eye anomalies (MIM253800; Fukuyama congenital muscular dystrophy = FCMD); a less severe congenital form without intellectual disability (MIM613152); and a milder limb-girdle form (MIM611588). In addition, FKTN mutations can also cause dilated cardiomyopathy (CMD1X; MIM611615) with or without limb-girdle muscle involvement.

Case Report: Here, we report on two brothers of first cousin Turkish parents who showed first symptoms at the age of 3 years: elevated creatine kinase levels (400–4,800 U/l) and mild, non-progressive proximal muscle weakness. The older brother underwent cardiac transplantation due to dilated cardiomyopathy at the age of 14. The younger developed cardiomyopathy at the age of 14 and is currently under cardiac medication at the age of 15. Intellectual performance of both brothers is within the lower normal range. cMR imaging and EEG are normal. Muscle biopsy showed a mild muscular dystrophy. Immunolabeling of α-dystroglycan was negative. Haplotype analysis for genes possibly involved in α-dystroglycanopathies pointed to a homozygous defect of FKTN. MLPA and PCR revealed a homozygous deletion of FKTN exon 3.

Conclusion: The majority of the CMD1X patients harbors a 3-kb insertion in the 3′ non-coding region of FKTN, a Japanese founder mutation, either homozygous or compound heterozygous with a FKTN missense mutation. However, rare biallelic truncating FKTN mutations so far were predominantly associated with FCMD, the most severe clinical manifestation. Here, we report a new FKTN alteration, a homozygous deletion of exon 3, which causes the mild phenotype of CMD1X in two brothers of consanguineous Turkish origin.