Primary ciliary dyskinesia (PCD) is an autosomal-recessive disorder characterized by impaired ciliary function that leads to subsequent clinical phenotypes such as chronic sinopulmonary disease. PCD is also a genetically heterogeneous disorder with many single gene mutations leading to similar clinical phenotypes. Here, we present a novel PCD causal gene, coiled-coil domain containing 151 (CCDC151), which has been shown to be essential in motile cilia of many animals and other vertebrates but its effects in humans was not observed until currently. We observed a novel nonsense mutation in a homozygous state in the CCDC151 gene (NM_145045.4:c.925G>T:p.[E309*]) in a clinically diagnosed PCD patient from a consanguineous family of Arabic ancestry. The variant was absent in 238 randomly selected individuals indicating that the variant is rare and likely not to be a founder mutation. Our finding also shows that given prior knowledge from model organisms, even a single whole-exome sequence can be sufficient to discover a novel causal gene.
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http://dx.doi.org/10.1002/humu.22698 | DOI Listing |
World J Surg Oncol
January 2025
Department of Otorhinolaryngology Head and Neck Surgery, Beijing Tiantan Hospital, Capital Medical University, No. 119, South Fourth Ring Road West, Fengtai District, Beijing, 100070, China.
Background: This study aims to identify a pathogenic SDHD mutation associated with hereditary head and neck paraganglioma (HNPGL) in a Chinese family and to explore its implications for genetic counseling.
Methods: The study involved a family with 15 members spanning three generations. A 31-year-old patient (II-4) was diagnosed with a left parotid gland tumor and a right carotid body tumor, while both the father and elder sister had right carotid body tumors, and the third sister had bilateral carotid body tumors.
Am J Hum Genet
January 2025
Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
Each human genome has approximately 5 million DNA variants. Even for complete loss-of-function variants causing inherited, monogenic diseases, current understanding based on gene-specific molecular function does not adequately predict variability observed between people with identical mutations or fluctuating disease trajectories. We present a parallel paradigm for loss-of-function variants based on broader consequences to the cell when aberrant polypeptide chains of amino acids are translated from mutant RNA to generate mutated proteins.
View Article and Find Full Text PDFAlzheimers Dement
December 2024
Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, FL, USA.
Background: Common and rare variants in SORL1 have been associated with increased risk of Alzheimer's disease (AD). Since 2019, we have run an international collaborative research initiative to ascertain a Peruvian cohort for Alzheimer's disease and other related dementias for genetic studies (PeADI).
Method: A Peruvian family (4 AD cases and two mild cognitive impairment (MCI) cases) was recruited through the PeADI study.
Alzheimers Dement
December 2024
Fujirebio Europe N.V., Ghent, Belgium.
Background: Apolipoprotein E (APOE) ε4 is a significant genetic risk factor for late-onset Alzheimer's Disease and appears to be closely related with brain amyloidosis. Current identification methods for APOE ε4 carriers are mostly based on genotyping which cannot always predict the specific ApoE protein isoform. We present a case study of a sample with a discordant result for genotype compared to the protein isoform (proteotype) and we reflect on possible implications for future applications.
View Article and Find Full Text PDFAlzheimers Dement
December 2024
Complex Genetics of Alzheimer's Disease group, VIB-UAntwerp Center for Molecular Neurology, Antwerp, Belgium.
Background: ABCA7, an important risk gene for AD, encodes a transporter implicated in lipid transport and phagocytosis, and its disruptions have been linked to AD pathogenesis. However, the impact of these mutations on AD risk is complex due to their interaction with a multifaceted transcriptional architecture and cell type-specificexpression patterns. This study aims to analyze the intricate patterns of ABCA7 expression across diverse cell types, considering various ABCA7 genotypes in relation to AD patients and non-carrier controls, while also exploring the effects of ABCA7 mutations on transcriptome-wide gene expression.
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