RESUMEN
Pathogenic variants in TRAF7 are often de novo and features of individuals harboring these variants are characterized by neurodevelopmental delay, ptosis, cardiac defects, limb anomalies, and dysmorphic features. We present a familial case in two African American patients with a novel, likely pathogenic c.1936G>A variant in TRAF7. Patient 1 is a 31-year-old female with a patent ductus arteriosus (PDA), intellectual disability, ptosis, and other dysmorphic features. She was identified to harbor this likely pathogenic variant in a mosaic (33.89%) state in leukocytes. Her son, Patient 2, is a 10-month-old male with a PDA, atrial septal defect, ptosis, developmental delay, history of feeding difficulties, congenital maxillary frenulum, and malrotation of the intestine. He has the same variant in a non-mosaic state. These cases demonstrate the variable expressivity observed with variants in TRAF7 within the same family and expand upon current understanding of mosaic TRAF7 variants. They also provide phenotypic data on genetic variation in individuals with African American ancestry, a population who has been underrepresented in the literature and may be less frequently referred to genetic specialists.
Asunto(s)
Blefaroptosis , Conducto Arterioso Permeable , Defectos del Tabique Interatrial , Discapacidad Intelectual , Anomalías Musculoesqueléticas , Síndrome de Circulación Fetal Persistente , Adulto , Femenino , Humanos , Lactante , Masculino , Negro o Afroamericano/genética , Discapacidades del Desarrollo/genética , Discapacidad Intelectual/genética , Péptidos y Proteínas Asociados a Receptores de Factores de Necrosis TumoralRESUMEN
Genomic testing increasingly challenges health care providers and patients to understand, share, and use information. The provision of polygenic risks is anticipated to complicate comprehension, communication, and risk perception further. This manuscript aims to illuminate the challenges confronting families with multiple genetic risks for Parkinson's disease. Identifying and planning for such issues may prove valuable to family members now and in the future, should neuroprotective or genotype-specific therapies become available. We present qualitative data from interviews with a multi-generational family carrying pathogenic variants in the glucocerebrosidase (GBA1) and leucine-rich repeat kinase 2 (LRRK2) genes which are associated with an increased risk for developing Parkinson's disease (PD). The family includes two brothers (heterozygous for LRRK2 p.G2019S and homozygous for GBA1 p.N409S) and their four descendants. The brothers were concordant for GD and discordant for PD. Genetic counseling and testing were provided to four of the six participants. Two years later, semi-structured interviews were conducted with the initial participants (n = 4) and two additional first-degree relatives. Interviews were transcribed and thematically analyzed, providing the basis for this report. Illuminated topics include the perceived risk of developing PD, recall of genetic information, and family communication. With the expanding use of exome and genome sequencing, we anticipate that genetic counselors will increasingly face the challenges demonstrated by this case involving multiple genetic risks for PD, limited data to clarify risk, and the inherent variability of family communication, genetic knowledge, and risk perception. This clinical case report provides a compelling narrative demonstrating the need for additional research exploring these multifaceted topics relevant to both families facing these challenges and providers striving to assist, support and guide their journey.
Asunto(s)
Enfermedad de Parkinson , Proteínas Serina-Treonina Quinasas , Masculino , Humanos , Proteínas Serina-Treonina Quinasas/genética , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/genética , Enfermedad de Parkinson/genética , Mutación , ComunicaciónRESUMEN
Gaucher disease (GD), resulting from biallelic mutations in the gene GBA1, is a monogenic recessively inherited Mendelian disorder with a wide range of phenotypic presentations. The more severe forms of the disease, acute neuronopathic GD (GD2) and chronic neuronopathic GD (GD3), also have a continuum of disease severity with an overlap in manifestations and limited genotype-phenotype correlation. In very young patients, assigning a definitive diagnosis can sometimes be challenging. Several recent studies highlight specific features of neuronopathic GD that may provide diagnostic clues. Distinguishing between the different GD types has important therapeutic implications. Currently there are limited treatment options specifically for neuronopathic GD due to the difficulty in delivering therapies across the blood-brain barrier. In this work, we present both classic and newly appreciated aspects of the Gaucher phenotype that can aid in discriminating between acute and chronic neuronopathic GD, and highlight the continuing therapeutic challenges.
Asunto(s)
Enfermedad de Gaucher/diagnóstico , Glucosilceramidasa/genética , Barrera Hematoencefálica/efectos de los fármacos , Enfermedad de Gaucher/clasificación , Enfermedad de Gaucher/tratamiento farmacológico , Enfermedad de Gaucher/genética , Estudios de Asociación Genética , Humanos , Fenotipo , Índice de Severidad de la EnfermedadRESUMEN
To support cell survival, mitochondria must balance energy production with oxidative stress. Inner ear hair cells are particularly vulnerable to oxidative stress; thus require tight mitochondrial regulation. We identified a novel molecular regulator of the hair cells' mitochondria and survival: Pregnancy-associated plasma protein-aa (Pappaa). Hair cells in zebrafish pappaa mutants exhibit mitochondrial defects, including elevated mitochondrial calcium, transmembrane potential, and reactive oxygen species (ROS) production and reduced antioxidant expression. In pappaa mutants, hair cell death is enhanced by stimulation of mitochondrial calcium or ROS production and suppressed by a mitochondrial ROS scavenger. As a secreted metalloprotease, Pappaa stimulates extracellular insulin-like growth factor 1 (IGF1) bioavailability. We found that the pappaa mutants' enhanced hair cell loss can be suppressed by stimulation of IGF1 availability and that Pappaa-IGF1 signaling acts post-developmentally to support hair cell survival. These results reveal Pappaa as an extracellular regulator of hair cell survival and essential mitochondrial function.