A novel mutation in FNIP1 associated with a syndromic immunodeficiency and cardiomyopathy.

Genetic variants in Folliculin interacting protein 1 (FNIP1) were recently discovered as monogenic causes for immunodeficiency and cardiomyopathy, with only a few patients diagnosed thus far. In this study, we describe a patient harboring a novel genetic variant in FNIP1 causing immunodeficiency with cardiac involvement. Clinical and immunological workups were performed. Genetic evaluation utilizing whole-exome sequencing (WES) and Sanger sequencing was conducted. The index patient (subject II-4) presented with hypertrophic cardiomyopathy, recurrent infections, and chronic diarrhea during infancy. Immune workup revealed agammaglobulinemia and a lack of B lymphocytes. Genetic evaluation identified a homozygous 13-bp duplication variant in FNIP1 (c.52_64dupGCGCCCGGCCGCG, p. Asp22GlyfsTer21) resulting in a frameshift in exon 1/18. She was treated with supplemental intravenous immunoglobulins (IVIg) with good control of sinopulmonary and gastrointestinal manifestations. Her sibling (subject II-1) had similar clinical features, along with dysmorphic facial features and hypotony, and succumbed to cardiogenic shock at the age of 2 months, prior to genetic evaluation. Diagnosis of novel immunodeficiencies promotes our understanding of the immune system, enabling genetic counseling as herein, and may assist in the development of novel medical therapies in the future. FNIP1 loss-of-function should be considered in patients presenting in infancy with cardiac manifestations along with agammaglobulinemia (and B-cell lymphopenia).