Phenotypic heterogeneity associated with KIF21A: Two new cases and review of the literature.

Our understanding of genetic and phenotypic heterogeneity associated with the clinical spectrum of rare diseases continues to expand. Thorough phenotypic descriptions and model organism functional studies are valuable tools in dissecting the biology of the disease process. Kinesin genes are well known to be associated with specific disease phenotypes and a subset of kinesin genes, including KIF21A, have been associated with more than one disease. Here we report two patients with KIF21A variants identified by exome sequencing; one with biallelic variants, supporting a novel KIF21A related syndrome with recessive inheritance and the second report of this condition, and another with a heterozygous de novo variant allele representing a phenotypic expansion of the condition described to date. We provide detailed phenotypic information on both families, including a novel neuropathology finding of neuroaxonal dystrophy associated with biallelic variants in KIF21A. Additionally, we studied the dominant variant in Saccharomyces cerevisiae to assess variant pathogenicity and found that this variant appears to impair protein function. KIF21A associated disease has mounting evidence for phenotypic heterogeneity; further patients and study of an allelic series are required to define the phenotypic spectrum and further explore the molecular etiology for each of these conditions.

Myopathy With SQSTM1 and TIA1 Variants: Clinical and Pathological Features.

OBJECTIVE: The aim of this study is to identify the molecular defect of three unrelated individuals with late-onset predominant distal myopathy; to describe the spectrum of phenotype resulting from the contributing role of two variants in genes located on two different chromosomes; and to highlight the underappreciated complex forms of genetic myopathies. PATIENTS AND METHODS: Clinical and laboratory data of three unrelated probands with predominantly distal weakness manifesting in the sixth-seventh decade of life, and available affected and unaffected family members were reviewed. Next-generation sequencing panel, whole exome sequencing, and targeted analyses of family members were performed to elucidate the genetic etiology of the myopathy. RESULTS: Genetic analyses detected two contributing variants located on different chromosomes in three unrelated probands: a heterozygous pathogenic mutation in SQSTM1 (c.1175C>T, p.Pro392Leu) and a heterozygous variant in TIA1 (c.1070A>G, p.Asn357Ser). The affected fraternal twin of one proband also carries both variants, while the unaffected family members harbor one or none. Two unrelated probands (family 1, II.3, and family 3, II.1) have a distal myopathy with rimmed vacuoles that manifested with index extensor weakness; the other proband (family 2, I.1) has myofibrillar myopathy manifesting with hypercapnic respiratory insufficiency and distal weakness. CONCLUSION: The findings indicate that all the affected individuals have a myopathy associated with both variants in SQSTM1 and TIA1, respectively, suggesting that the two variants determine the phenotype and likely functionally interact. We speculate that the TIA1 variant is a modifier of the SQSTM1 mutation. We identify the combination of SQSTM1 and TIA1 variants as a novel genetic defect associated with myofibrillar myopathy and suggest to consider sequencing both genes in the molecular investigation of myopathy with rimmed vacuoles and myofibrillar myopathy although additional studies are needed to investigate the digenic nature of the disease.

Synchronous appendiceal and intramucosal gastric signet ring cell carcinomas in an individual with CDH1-associated hereditary diffuse gastric carcinoma: a case report of a novel association and review of the literature.

BACKGROUND: Hereditary diffuse gastric carcinoma is an autosomal dominant cancer syndrome associated with mutations of the E-cadherin gene (CDH1). E-cadherin is normally involved in cell-cell adhesion, so it not surprising that individuals with this syndrome are predisposed to develop malignancies with dyshesive morphologies at a young age, such as diffuse (signet ring cell) gastric carcinoma and lobular breast carcinoma. Herein we describe the first reported case of primary appendiceal signet ring cell carcinoma arising in a CDH1-associated hereditary diffuse gastric carcinoma kindred with synchronous primary diffuse gastric carcinoma. CASE PRESENTATION: A 51- year old woman, with known CDH1 mutation carrier status and a prior history of lobular breast carcinoma underwent prophylactic total gastrectomy which revealed multifocal intramucosal signet ring cell carcinoma. An appendectomy was performed at the same time due to a prior episode of presumed appendicitis, with pathologic examination significant for a primary signet ring cell carcinoma of the appendix. CONCLUSION: As appendiceal signet ring cell carcinoma is exceedingly rare, the occurrence of this neoplasm in this patient, with this particular morphology, provides credence for it being part of the hereditary diffuse gastric carcinoma spectrum of malignancies.

"Grown-up" congenital heart disease and sudden death in a medical examiner's population.

Despite advances in the management of congenital heart disease (CHD), children with CHD who survive into adulthood are at increased risk of sudden death. Sudden death may also be the initial presentation of undiagnosed CHD in some adults. This retrospective descriptive study outlines the spectrum of CHD presenting as sudden death in adults in a medical examiner's population. Despite its rarity (0.2% of all cases investigated between 1991 and 2007), CHD remains an important cause of sudden cardiac death to be recognized at adult autopsy. Bicuspid aortic valve and anomalous coronary anomalies were the most common malformations, comprising 36.9% and 26.2% of cases, respectively. However, a wide spectrum of simple to complex malformations can be seen, with or without prior surgery, and over a wide age spectrum. Once solely a pediatric entity, CHD is now "grown-up" and will likely be diagnosed by forensic pathologists with increased frequency in the future.