RESUMEN
Genetic workup is becoming increasingly common in the clinical assessment of neurological disorders. We evaluated its yield among middle-aged and elderly neurological patients, in a real-world context. This retrospective study included 368 consecutive Israeli patients aged 50 years and older (202 [54.9%] males), who were referred to a single neurogenetics clinic between 2017 and mid-2023. All had neurological disorders, without a previous molecular diagnosis. Demographic, clinical and genetic data were collected from medical records. The mean age at first genetic counseling at the clinic was 62.3 ± 7.8 years (range 50-85 years), and the main indications for referral were neuromuscular, movement and cerebrovascular disorders, as well as cognitive impairment and dementia. Out of the 368 patients, 245 (66.6%) underwent genetic testing that included exome sequencing (ES), analysis of nucleotide repeat expansions, detection of specific mutations, targeted gene panel sequencing or chromosomal microarray analysis. Overall, 80 patients (21.7%) received a molecular diagnosis due to 36 conditions, accounting for 32.7% of the patients who performed genetic testing. The diagnostic rates were highest for neuromuscular (58/186 patients [31.2%] in this group, 39.2% of 148 tested individuals) and movement disorders (14/79 [17.7%] patients, 29.2% of 48 tested), but lower for other disorders. Testing of nucleotide repeat expansions and ES provided a diagnosis to 28/73 (38.4%) and 19/132 (14.4%) individuals, respectively. Based on our findings, genetic workup and testing are useful in the diagnostic process of neurological patients aged ≥50 years, in particular for those with neuromuscular and movement disorders.
Asunto(s)
Pruebas Genéticas , Enfermedades del Sistema Nervioso , Humanos , Anciano , Masculino , Femenino , Persona de Mediana Edad , Anciano de 80 o más Años , Estudios Retrospectivos , Enfermedades del Sistema Nervioso/genética , Enfermedades del Sistema Nervioso/diagnóstico , Enfermedades del Sistema Nervioso/epidemiología , Pruebas Genéticas/métodos , Israel/epidemiologíaRESUMEN
Mutated skeletal muscle ryanodine receptor-1 (RYR1) gene is associated with a spectrum of autosomal dominant and recessive RyR1-related disorders with a wide phenotype. This report describes a variable phenotype associated with a previously unreported RYR1 frameshift pathogenic variant, (NM_000540.2) c.12815_12825del; p.Ala4272Glyfs*307, common in Libyan Jews. Clinical and genetic features of 14 carriers from 8 unrelated families were collected. There were 12 heterozygotes and 2 compound heterozygotes. Six heterozygotes (median age 49.8) were asymptomatic, and six (median age 24.5) presented with myopathy (n = 3) or severe arthrogryposis-like features, severe scoliosis, pes planus, post-anesthesia malignant hyperthermia, or cystic hygroma (in a fetus) (n = 1 each). None had an abnormal echocardiogram study or elevated creatine phosphokinase (CPK) levels. One bi-allelic carrier had a severe skeletal phenotype and myopathy; the other was a fetus with a cystic hygroma. Assessment of variant frequency in 447 Libyan Jews who underwent exome testing for unrelated reason yielded a prevalence of 1:55. The RYR1 p.Ala4272Glyfs*307 variant is common in Libyan Jews. It is associated with a broad phenotypic spectrum, with possible presentation among heterozygotes. Further genotype-phenotype studies are essential to delineate the clinical significance of the variant in mono- and bi-allelic carriers.
Asunto(s)
Heterocigoto , Judíos , Fenotipo , Canal Liberador de Calcio Receptor de Rianodina , Humanos , Canal Liberador de Calcio Receptor de Rianodina/genética , Femenino , Masculino , Libia , Adulto , Persona de Mediana Edad , Judíos/genética , Adulto Joven , Adolescente , Mutación del Sistema de Lectura , Niño , Enfermedades Musculares/genética , AncianoRESUMEN
OBJECTIVE: Significant discrepancy exists between laboratories in classification and reporting of copy number variants (CNVs). Studies exploring factors affecting prenatal CNV management are rare. Our "virtual fetus" pilot study examines these factors. METHOD: Ten prenatally diagnosed CNVs of uncertain significance (VUS) > 1Mb, encompassing OMIM-morbid genes, inherited from healthy parents, were classified by 15 MD geneticists from laboratory, prenatal, and preimplantation genetic testing (PGT) units. Geneticists addressed factors affecting classification, obligation to report, and recommendation for invasive testing or PGT. RESULTS: CNVs were classified likely benign (10.7%), VUS (74.7%), likely pathogenic (8.7%), or pathogenic (6.0%). Classification discrepancy was higher for losses versus gains. Classifying pathogenic/likely pathogenic was more common for losses (adjusted odds ratio [aOR] 10.9, 95% CI 1.55-76.9), and geneticists specializing in gynecology (aOR 4.9, 95% CI 1.03-23.3). 84.0% of respondents would report CNVs, depending on classification and family phenotype. Invasive testing in pregnancies was recommended for 29.3% of CNVs, depending on the classification and geneticist's specialization. PGT was recommended for 32.4%, depending on classification, experience years, and family's phenotype (38.0% for patients undergoing in vitro fertilization irrespectively, 26.7% otherwise). CONCLUSION: Factors affecting CNV classification/reporting are mainly dosage, family phenotype, geneticist specialization and experience. Understanding factors from our pilot study may facilitate developing an algorithm for clinical consensus and optimal management.
Asunto(s)
Variaciones en el Número de Copia de ADN , Feto , Femenino , Embarazo , Humanos , Proyectos Piloto , Análisis por Micromatrices , FenotipoRESUMEN
Exome sequencing (ES) is an important diagnostic tool for individuals with neurodevelopmental disorders (NDD) and/or multiple congenital anomalies (MCA). However, the cost of ES limits the test's accessibility for many patients. We evaluated the yield of publicly funded clinical ES, performed at a tertiary center in Israel, over a 3-year period (2018-2020). Probands presented with (1) moderate-to-profound global developmental delay (GDD)/intellectual disability (ID); or (2) mild GDD/ID with epilepsy or congenital anomaly; and/or (3) MCA. Subjects with normal chromosomal microarray analysis who met inclusion criteria were included, totaling 280 consecutive cases. Trio ES (proband and parents) was the default option. In 252 cases (90.0%), indication of NDD was noted. Most probands were males (62.9%), and their mean age at ES submission was 9.3 years (range 1 month to 51 years). Molecular diagnosis was reached in 109 probands (38.9%), mainly due to de novo variants (91/109, 83.5%). Disease-causing variants were identified in 92 genes, 15 of which were implicated in more than a single case. Male sex, families with multiple-affected members and premature birth were significantly associated with lower ES yield (p < 0.05). Other factors, including MCA and coexistence of epilepsy, autism spectrum disorder, microcephaly or abnormal brain magnetic resonance imaging findings, were not associated with the yield. To conclude, our findings support the utility of clinical ES in a real-world setting, as part of a publicly funded genetic workup for individuals with GDD/ID and/or MCA.
Asunto(s)
Anomalías Múltiples/diagnóstico , Secuenciación del Exoma/economía , Financiación Gubernamental , Pruebas Genéticas/economía , Trastornos del Neurodesarrollo/diagnóstico , Anomalías Múltiples/economía , Anomalías Múltiples/genética , Adolescente , Adulto , Niño , Preescolar , Análisis Costo-Beneficio , Estudios de Factibilidad , Femenino , Asesoramiento Genético/economía , Asesoramiento Genético/métodos , Asesoramiento Genético/estadística & datos numéricos , Pruebas Genéticas/métodos , Pruebas Genéticas/estadística & datos numéricos , Humanos , Lactante , Recién Nacido , Israel , Masculino , Edad Materna , Trastornos del Neurodesarrollo/economía , Trastornos del Neurodesarrollo/genética , Edad Paterna , Embarazo , Diagnóstico Prenatal/economía , Diagnóstico Prenatal/métodos , Evaluación de Programas y Proyectos de Salud , Estudios Retrospectivos , Centros de Atención Terciaria/economía , Centros de Atención Terciaria/estadística & datos numéricos , Secuenciación del Exoma/estadística & datos numéricos , Adulto JovenRESUMEN
Lymphatic-venous malformations (LVMs) are development defects that result in abnormal connections between the lymphatic and venous systems. The authors describe a 7-weeks-old female infant who presented with a right orbital LVM extending to the ipsilateral cheek and subconjunctiva of the right eye, intracranial developmental venous anomalies in the right cerebellum, and a significant right eye intraocular retinal vascular malformation. Since orbital LVM is usually diagnosed in infancy or childhood, pediatric ophthalmologists should actively look for intraocular vascular malformations as such findings can poorly affect a patient's vision.
Asunto(s)
Trastornos de la Motilidad Ciliar/genética , Encefalocele/genética , Efecto Fundador , Judíos/genética , Proteínas de la Membrana/genética , Enfermedades Renales Poliquísticas/genética , Retinitis Pigmentosa/genética , Trastornos de la Motilidad Ciliar/epidemiología , Trastornos de la Motilidad Ciliar/patología , Encefalocele/epidemiología , Encefalocele/patología , Etiopía/epidemiología , Femenino , Humanos , Masculino , Enfermedades Renales Poliquísticas/epidemiología , Enfermedades Renales Poliquísticas/patología , Retinitis Pigmentosa/epidemiología , Retinitis Pigmentosa/patología , Yemen/epidemiologíaRESUMEN
Prenatal ultrasound (US) abnormalities often pose a clinical dilemma and necessitate facilitated investigations in the search of diagnosis. The strategy of pursuing fetal whole-exome sequencing (WES) for pregnancies complicated by abnormal US findings is gaining attention, but the reported diagnostic yield is variable. In this study, we describe a tertiary center's experience with fetal WES from both terminated and ongoing pregnancies, and examine the clinical factors affecting the diagnostic rate. A total of 45 consecutive families of Jewish descent were included in the analysis, for which clinical fetal WES was performed under either single (fetus only), trio (fetus and parents) or quatro (two fetuses and parents) design. Except one, all families were non-consanguineous. In 41 of the 45 families, WES was sought following abnormal fetal US findings, and 18 of them had positive relevant family history (two or more fetuses with US abnormalities, or single fetus with US abnormalities and an affected parent). The overall diagnostic yield was 28.9% (13/45 families), and 31.7% among families with fetal US abnormalities (13/41). It was significantly higher in families with prenatal US abnormalities and relevant family history (10/18, 55.6%), compared to families with prenatal US abnormal findings and lack of such history (3/23, 13%) (p = 0.004). WES yield was relatively high (42.9-60%) among families with involvement of brain, renal or musculoskeletal US findings. Taken together, our results in a real-world setting of genetic counseling demonstrates that fetal WES is especially indicated in families with positive family history, as well as in fetuses with specific types of congenital malformation.
RESUMEN
Hajdu Cheney syndrome is a rare autosomal dominant skeletal dysplasia, with multi-organ involvement, caused by pathogenic variants in NOTCH2. It is characterized by progressive focal bone destruction, including acro-osteolysis and generalized osteoporosis, craniofacial anomalies, hearing loss, cardiovascular involvement and polycystic kidneys. Distinct radiographic findings, such as a serpentine fibula, may aid in facilitating the diagnosis. Despite several dozens of cases described in the literature, diagnosis often remains elusive, resulting in many cases in a delay in diagnosis reaching adolescence or adulthood. We report herein two unrelated patients of Turkish/Lebanese Jewish and Ashkenazi Jewish descent, each presenting with distinct clinical challenges and subsequently distinct diagnostic odysseys leading to their molecular diagnosis. These illustrative clinical descriptions underscore the wide phenotypic variability of HCS, and further contribute to the current knowledge regarding this rare entity.
Asunto(s)
Síndrome de Hajdu-Cheney/genética , Fenotipo , Adolescente , Femenino , Síndrome de Hajdu-Cheney/patología , Humanos , Masculino , Receptor Notch2/genéticaRESUMEN
Adhesion of epithelial cell to each other and to extracellular matrix, as well as cell migration ability and cytoskeleton organization undergo significant alterations in the course of neoplastic transformation, but regulatory mechanisms involved in these processes are not fully understood. Here, we studied the role of a Rho GAP protein GRAF1 (GTPase Regulator Associated with Focal adhesion kinase-1) in the regulation of the epithelial phenotype in cells of breast derived, non-malignant, MCF10A cell line. GRAF1 was shown to be localized to cell-cell junctions, and its depletion resulted in accelerated cell migration velocity, elongation of the cells and cell colonies, impaired monolayer integrity and significant disruption of desmosomes with a loss of associated keratin filaments. These processes were accompanied by formation of larger focal adhesions, an increased number of contractile actin stress fibers, reduction in epithelial markers and increase in mesenchymal markers such as epithelial-mesenchymal transition (EMT)-specific transcription factors Snail-1 and Snail-2, as well as N-cadherin, and vimentin. Moreover, unlike control cells, GRAF1 knocked-down cells demonstrated anchorage-independent growth in soft agar. GRAF1 expression in several highly invasive breast cancer cell lines was low, as compared to the non-malignant MCF10A cells, while overexpressing of GRAF1 in the malignant BT-549 cell line led to a decrease of mesenchymal markers, especially the Snail-1 and 2. Altogether, our analysis suggests that GRAF1 plays a role in the maintenance of normal epithelial phenotype and its depletion leads to an EMT-like process that might be involved in neoplastic transformation.
Asunto(s)
Células Epiteliales/patología , Proteínas Activadoras de GTPasa/metabolismo , Citoesqueleto de Actina/metabolismo , Agar , Biomarcadores/metabolismo , Adhesión Celular , Línea Celular Tumoral , Movimiento Celular , Forma de la Célula , Células Epiteliales/metabolismo , Células Epiteliales/ultraestructura , Transición Epitelial-Mesenquimal , Adhesiones Focales/metabolismo , Geles , Técnicas de Silenciamiento del Gen , Humanos , Uniones Intercelulares/metabolismo , Uniones Intercelulares/ultraestructura , Lentivirus/metabolismo , Mesodermo/metabolismo , Invasividad Neoplásica , Fenotipo , ARN Interferente Pequeño/metabolismo , Proteína de Unión al GTP rac1/metabolismo , Quinasas Asociadas a rho/antagonistas & inhibidores , Quinasas Asociadas a rho/metabolismoRESUMEN
Autoimmune diseases are classic examples of multifactorial disorders in which a large number of genes interact with environmental factors to form the final phenotype. Identification of the genes involved in these diseases is a daunting challenge. Initially the search involved the candidate approach where polymorphisms in suspected genes were tested for association in large cohorts of patients and controls. Today, the most widely used method is genome-wide association studies (GWAS), a method based on screening large panels of patients and controls with hundreds of thousands of single nucleotide polymorphisms (SNPs), using microarray-based technology. Unique families in which autoimmune diseases are caused by single genes are another alternative. The identification of candidate genes is often followed by studies that provide biologic plausibility for the findings. The widely expanding list of genes involved in autoimmune conditions show that the same genes frequently underlie the pathogenesis of different autoimmune diseases. Despite all available resources, the main void of heritability in autoimmune conditions is yet to be discovered. Identification of these genes will help define new biological pathways and identify novel targets for the development of new therapeutic drugs.
Asunto(s)
Autoinmunidad/genética , Interacción Gen-Ambiente , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , HumanosRESUMEN
Congenital myopathies are heterogeneous inherited diseases of muscle characterized by a range of distinctive histologic abnormalities. We have studied a consanguineous family with congenital myopathy. Genome-wide linkage analysis and whole-exome sequencing identified a homozygous non-sense mutation in 3-hydroxyacyl-CoA dehydratase 1 (HACD1) in affected individuals. The mutation results in non-sense mediated decay of the HACD1 mRNA to 31% of control levels in patient muscle and completely abrogates the enzymatic activity of dehydration of 3-hydroxyacyl-CoA, the third step in the elongation of very long-chain fatty acids (VLCFAs). We describe clinical findings correlated with a deleterious mutation in a gene not previously known to be associated with congenital myopathy in humans. We suggest that the mutation in the HACD1 gene causes a reduction in the synthesis of VLCFAs, which are components of membrane lipids and participants in physiological processes, leading to congenital myopathy. These data indicate that HACD1 is necessary for muscle function.
Asunto(s)
Enfermedades Musculares/genética , Miopatías Estructurales Congénitas/genética , Proteínas Tirosina Fosfatasas/genética , Estabilidad del ARN/genética , Adolescente , Adulto , Secuencia de Aminoácidos , Niño , Preescolar , Consanguinidad , Exoma/genética , Ácidos Grasos/metabolismo , Femenino , Ligamiento Genético , Secuenciación de Nucleótidos de Alto Rendimiento , Homocigoto , Humanos , Lactante , Masculino , Enfermedades Musculares/fisiopatología , Mutación , Miopatías Estructurales Congénitas/fisiopatología , Linaje , Proteínas Tirosina Fosfatasas/metabolismoRESUMEN
The Aristaless Related Homeobox (ARX) gene is a Q(50) paired homeobox gene. These genes are important regulators of essential events during vertebrate embryogenesis, including the development of the central and peripheral nervous system. Mutations in ARX have been identified in at least 82 different families and sporadic cases, and are responsible for at least 8 clinically distinct disorders. The recurrent 24 bp duplication (dup) mutation, c.429_452dup(24 bp), is the most frequent ARX mutation, which accounts for 45% of all cases reported to date. Here we report a novel de novo, familial dup mutation of 27 bp, c.430_456dup(27 bp), which involves the same region of the ARX gene in exon 2, as the dup24 bp mutation. The female progenitor of this dup27 bp allele exhibits mosaicism, likely resulting from a postmitotic de novo mutation event early in embryonic development. Three males with the dup27 bp mutation presented with infantile spasms, two of whom died early in life. Their phenotype appeared more severe, when compared to the spectrum of clinical presentations associated with the dup24 bp mutation. We propose that this might be at least partly due to the single, extra alanine residue (A) (21A in dup27 vs. 20A in dup24), which takes polyalanine tract 2 of ARX beyond the maximum, naturally occurring limit of 20A found in the human genome.
Asunto(s)
Emparejamiento Base/genética , Duplicación de Gen , Proteínas de Homeodominio/genética , Mosaicismo/embriología , Factores de Transcripción/genética , Cigoto/metabolismo , Adulto , Secuencia de Aminoácidos , Secuencia de Bases , Preescolar , Análisis Mutacional de ADN , Composición Familiar , Femenino , Proteínas de Homeodominio/química , Humanos , Lactante , Masculino , Datos de Secuencia Molecular , Linaje , Fenotipo , Síndrome , Factores de Transcripción/químicaRESUMEN
Niemann-Pick type C (NPC) disease is a lysosomal neurovisceral storage disease. The spectrum of the clinical presentation as well as the severity of the disease and the age of presentation may be highly variable. Fetal presentation is rarely described in the literature. Here, we report on seven new cases of fetal onset NPC of whom two were diagnosed in utero and five postnatally. The fetal clinical presentation, included, in utero splenomegaly (6/7), in utero hepatomegaly (5/7), in utero ascites (4/7), intra uterine growth retardation (IUGR) (2/7), and oligohydramnios (2/7). Placentomegaly was present in two of the three pregnancies examined. Congenital thrombocytopenia (4/4), congenital anemia (2/4), and petechial rash (2/5) were diagnosed immediately after birth. Three patients were born preterm. Pregnancy and postnatal outcome were remarkably poor with one case of intrauterine fetal death, one elective termination of pregnancy, and four patients who died within the first months of life from a rapidly fatal neonatal cholestatic disease. NPC1 gene mutation analysis identified all of the mutant alleles including three novel mutations. Splenomegaly, hepatomegaly, and ascites were the most consistent prenatal ultrasonographic findings of the NPC fetuses. We suggest that once identified these findings, should raise the suspicion of fetal NPC. Our study further expands the antenatal clinical spectrum of NPC and provides clues to its prenatal diagnosis.
Asunto(s)
Ascitis/genética , Proteínas Portadoras/genética , Hepatomegalia/genética , Enfermedades por Almacenamiento Lisosomal/genética , Glicoproteínas de Membrana/genética , Enfermedad de Niemann-Pick Tipo C/genética , Esplenomegalia/genética , Ascitis/diagnóstico por imagen , Análisis Mutacional de ADN , Femenino , Muerte Fetal , Feto , Hepatomegalia/diagnóstico por imagen , Humanos , Péptidos y Proteínas de Señalización Intracelular , Enfermedades por Almacenamiento Lisosomal/diagnóstico por imagen , Proteína Niemann-Pick C1 , Enfermedad de Niemann-Pick Tipo C/diagnóstico , Embarazo , Diagnóstico Prenatal , Esplenomegalia/diagnóstico por imagen , Ultrasonografía PrenatalRESUMEN
We present a vertical transmission of a nonsense mutation in exon 1 of the Wilms' tumor WT1 gene, from a mother who had Wilms' tumor in infancy and decreased fertility at adulthood, to her son who displayed genitourinary (GU) anomalies, gonadal dysgenesis with gonadoblastoma foci, and intra-abdominal Mullerian derivatives. No Wilms' tumor was detected up to the age of 6 years in the son. Sequence analysis of constitutional DNA of the WT1 gene revealed a heterozygous c.327C > A sequence change in exon 1 leading to a premature stop codon at amino acid 109. This mutation demonstrates the lack of correlation between genotype-phenotype and mutation position in the WT1 gene, the presence of intra-familial variability, and the effect of gender on severity of GU anomalies. We suggest that detection of a GU defect in the presence of parental history of Wilms' tumor be followed up by screening of constitutional DNA for WT1 mutations. Explorative laparoscopy for sex organ evaluation and gonadal assessment for possible gonadoblastoma should be considered when constitutional mutation is detected in males with GU anomalies.