Reversible Dilated Cardiomyopathy Caused by a High Burden of Ventricular Arrhythmias in Andersen-Tawil Syndrome.

Andersen-Tawil syndrome (ATS) is caused by mutations in KCNJ2 (Kir2.1). It remains unclear whether dilated cardiomyopathy (DCM) is a primary feature of ATS. We studied a proband with typical physical features of ATS plus DCM and moderate to severe left ventricular dysfunction (left ventricular ejection fraction = 30.5%). Genetic screening revealed a novel mutation in Kir2.1 (c.665T>C, p.L222S). Functional studies showed that this mutation reduced ionic currents in a dominant-negative manner. Suppression of ventricular arrhythmias with bisoprolol led to normalization of left ventricular size and function. We conclude that DCM is likely a secondary phenotype in ATS and is caused by high ventricular arrhythmia burden.

Mutations in FLNC are Associated with Familial Restrictive Cardiomyopathy.

Individuals affected by restrictive cardiomyopathy (RCM) often develop heart failure at young ages resulting in early heart transplantation. Familial forms are mainly caused by mutations in sarcomere proteins and demonstrate a common genetic etiology with other inherited cardiomyopathies. Using next-generation sequencing, we identified two novel missense variants (p.S1624L; p.I2160F) in filamin-C (FLNC), an actin-cross-linking protein mainly expressed in heart and skeletal muscle, segregating in two families with autosomal-dominant RCM. Affected individuals presented with heart failure due to severe diastolic dysfunction requiring heart transplantation in some cases. Histopathology of heart tissue from patients of both families showed cytoplasmic inclusions suggesting protein aggregates, which were filamin-C specific for the p.S1624L by immunohistochemistry. Cytoplasmic aggregates were also observed in transfected myoblast cell lines expressing this mutant filamin-C indicating further evidence for its pathogenicity. Thus, FLNC is a disease gene for autosomal-dominant RCM and broadens the phenotype spectrum of filaminopathies.

Gaucher disease with prenatal onset and perinatal death due to compound heterozygosity for the missense R131C and null Rec Nci I GBA mutations.

Gaucher disease is an autosomal recessive disorder resulting from deficient activity of the lysosomal enzyme glucocerebrosidase (GBA, E.C.3.2.1.45). Three clinical forms of Gaucher disease have been described: type 1, nonneuronopathic; type 2, acute neuronopathic; and type 3, subacute neuronopathic (OMIM 230800, 230900, 231000). Over the past decade, recognition of a distinct, perinatal lethal form of Gaucher disease (PLGD) has led researchers and clinicians to evaluate Gaucher disease in the differential diagnosis of congenital ichthyosis and nonimmune hydrops fetalis. To date, more than 30 cases of PLGD have been genotyped and reported. It has been observed that homozygosity for recombinant GBA alleles, which are fundamentally null alleles, leads to early lethality, usually in utero or during the 1st few days of life, whereas genotypes involving a recombinant allele and a missense mutation may be less detrimental. Here, we report a case of Gaucher disease with prenatal onset and death within hours of birth, likely due to compound heterozygosity for the GBA Rec Nci I null allele and a R131C missense mutation. In view of the patient's severe clinical course, and based on reviews of other PLGD cases, we postulate that a missense mutation that abruptly disrupts the structure/function of GBA, in combination with a null allele, may result in early lethality in patients with PLGD. We also speculate that R131C is an extremely severe mutation that has occurred more than once in different populations and, in either the homozygous form or heterozygous with another severe mutation, will result in a poor prognosis.