Case series: clinical outcomes of the transthyretin valine-to-isoleucine mutation in a brother-sister pair.

BACKGROUND: Approximately 4% of the African-American population possess a valine-to-isoleucine (V122I) substitution within the transthyretin protein that results in a tendency for a normally tetrameric protein to dissociate into misfolded, monomeric subunits. These misfolded proteins can then accumulate pathologically and cause an autosomal dominant amyloid cardiomyopathy. Homozygous patients are infrequently documented in case reports, and though there are larger studies among heterozygous patients, there is a lack of studies or reports comparing disease within a family. CASE SUMMARY: In this case series, we discuss a 61-year-old African-American male who succumbed to heart failure secondary to cardiac amyloidosis while awaiting orthotopic heart transplantation. We compare his case with that of his sister, a 65-year-old African-American woman with a history of recurrent supraventricular tachycardia requiring radiofrequency ablation, and intermittent chest pain with chronically elevated troponin despite no evidence of coronary artery disease. The sister in question was found to be homozygous for the transthyretin (TTR) V122I mutation with evidence of infiltrative process on cardiac magnetic resonance imaging, while clinical testing verified a heterozygous genotype in the brother. Here, we compare the clinical course and imaging data for the aforementioned brother-sister pair in the context of the amyloidogenic transthyretin V122I gene variant. DISCUSSION: Through this familial report, we aim to highlight the variations in expression both within this family and in comparison, to the population. We also hope to emphasize the importance of genetic testing of families at risk for this specific transthyretin variant within the African-American community especially as novel therapies begin to emerge.

De Novo Mutations in CHD4, an ATP-Dependent Chromatin Remodeler Gene, Cause an Intellectual Disability Syndrome with Distinctive Dysmorphisms.

Chromodomain helicase DNA-binding protein 4 (CHD4) is an ATP-dependent chromatin remodeler involved in epigenetic regulation of gene transcription, DNA repair, and cell cycle progression. Also known as Mi2ß, CHD4 is an integral subunit of a well-characterized histone deacetylase complex. Here we report five individuals with de novo missense substitutions in CHD4 identified through whole-exome sequencing and web-based gene matching. These individuals have overlapping phenotypes including developmental delay, intellectual disability, hearing loss, macrocephaly, distinct facial dysmorphisms, palatal abnormalities, ventriculomegaly, and hypogonadism as well as additional findings such as bone fusions. The variants, c.3380G>A (p.Arg1127Gln), c.3443G>T (p.Trp1148Leu), c.3518G>T (p.Arg1173Leu), and c.3008G>A, (p.Gly1003Asp) (GenBank: NM_001273.3), affect evolutionarily highly conserved residues and are predicted to be deleterious. Previous studies in yeast showed the equivalent Arg1127 and Trp1148 residues to be crucial for SNF2 function. Furthermore, mutations in the same positions were reported in malignant tumors, and a de novo missense substitution in an equivalent arginine residue in the C-terminal helicase domain of SMARCA4 is associated with Coffin Siris syndrome. Cell-based studies of the p.Arg1127Gln and p.Arg1173Leu mutants demonstrate normal localization to the nucleus and HDAC1 interaction. Based on these findings, the mutations potentially alter the complex activity but not its formation. This report provides evidence for the role of CHD4 in human development and expands an increasingly recognized group of Mendelian disorders involving chromatin remodeling and modification.