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1.
Am J Hum Genet ; 111(7): 1271-1281, 2024 07 11.
Artículo en Inglés | MEDLINE | ID: mdl-38843839

RESUMEN

There is mounting evidence of the value of clinical genome sequencing (cGS) in individuals with suspected rare genetic disease (RGD), but cGS performance and impact on clinical care in a diverse population drawn from both high-income countries (HICs) and low- and middle-income countries (LMICs) has not been investigated. The iHope program, a philanthropic cGS initiative, established a network of 24 clinical sites in eight countries through which it provided cGS to individuals with signs or symptoms of an RGD and constrained access to molecular testing. A total of 1,004 individuals (median age, 6.5 years; 53.5% male) with diverse ancestral backgrounds (51.8% non-majority European) were assessed from June 2016 to September 2021. The diagnostic yield of cGS was 41.4% (416/1,004), with individuals from LMIC sites 1.7 times more likely to receive a positive test result compared to HIC sites (LMIC 56.5% [195/345] vs. HIC 33.5% [221/659], OR 2.6, 95% CI 1.9-3.4, p < 0.0001). A change in diagnostic evaluation occurred in 76.9% (514/668) of individuals. Change of management, inclusive of specialty referrals, imaging and testing, therapeutic interventions, and palliative care, was reported in 41.4% (285/694) of individuals, which increased to 69.2% (480/694) when genetic counseling and avoidance of additional testing were also included. Individuals from LMIC sites were as likely as their HIC counterparts to experience a change in diagnostic evaluation (OR 6.1, 95% CI 1.1-∞, p = 0.05) and change of management (OR 0.9, 95% CI 0.5-1.3, p = 0.49). Increased access to genomic testing may support diagnostic equity and the reduction of global health care disparities.


Asunto(s)
Pruebas Genéticas , Enfermedades Raras , Secuenciación Completa del Genoma , Humanos , Masculino , Enfermedades Raras/genética , Enfermedades Raras/diagnóstico , Femenino , Niño , Pruebas Genéticas/métodos , Preescolar , Adolescente , Adulto , Lactante , Enfermedades Genéticas Congénitas/genética , Enfermedades Genéticas Congénitas/diagnóstico
2.
Am J Med Genet A ; 194(4): e63477, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-37969032

RESUMEN

Germline pathogenic variants in the RAS/mitogen-activated protein kinase (MAPK) signaling pathway are the molecular cause of RASopathies, a group of clinically overlapping genetic syndromes. RASopathies constitute a wide clinical spectrum characterized by distinct facial features, short stature, predisposition to cancer, and variable anomalies in nearly all the major body systems. With increasing global recognition of these conditions, the 8th International RASopathies Symposium spotlighted global perspectives on clinical care and research, including strategies for building international collaborations and developing diverse patient cohorts in anticipation of interventional trials. This biannual meeting, organized by RASopathies Network, was held in a hybrid virtual/in-person format. The agenda featured emerging discoveries and case findings as well as progress in preclinical and therapeutic pipelines. Stakeholders including basic scientists, clinician-scientists, practitioners, industry representatives, patients, and family advocates gathered to discuss cutting edge science, recognize current gaps in knowledge, and hear from people with RASopathies about the experience of daily living. Presentations by RASopathy self-advocates and early-stage investigators were featured throughout the program to encourage a sustainable, diverse, long-term research and advocacy partnership focused on improving health and bringing treatments to people with RASopathies.


Asunto(s)
Síndrome de Costello , Displasia Ectodérmica , Cardiopatías Congénitas , Neoplasias , Síndrome de Noonan , Humanos , Proteínas ras/genética , Sistema de Señalización de MAP Quinasas/genética , Síndrome de Costello/genética , Neoplasias/genética , Displasia Ectodérmica/genética , Síndrome de Noonan/genética , Cardiopatías Congénitas/genética
3.
Mol Genet Metab ; 139(3): 107609, 2023 07.
Artículo en Inglés | MEDLINE | ID: mdl-37245377

RESUMEN

The pediatric to adult healthcare transition (HCT) is a process for individuals with chronic health conditions to gradually shift from a pediatric to an adult-oriented care system. Autonomy and self-management skills required for an individual's HCT readiness can be evaluated through the transition readiness assessment questionnaire (TRAQ). Despite general HCT preparation guidelines, little is known about the HCT experience of individuals with a urea cycle disorder (UCD). This is the first study to report the parent or guardian perception of the HCT process in children with a UCD by investigating the stages of transition readiness and transition outcome. We identify barriers to HCT readiness and planning, along with deficiencies in transition outcome for individuals with a UCD. For children that received special education services compared to those that did not, significantly lower transition readiness scores were identified in the total TRAQ score (p = 0.03) and in the domains of tracking health issues (p = 0.02), talking with providers (p = 0.03), and managing daily activities (p = 0.01). There was a lack of HCT preparation as most subjects did not have a HCT discussion with their healthcare provider before age 26. Deficiencies in HCT outcome are demonstrated by individuals with a UCD reporting delays in needed medical care and dissatisfaction with their healthcare services. Considerations for facilitating a successful HCT for individuals with a UCD include providing individualized education, appointing a transition coordinator, allowing flexibility in HCT timing, and ensuring that the individual recognizes concerning UCD symptoms and knows when to seek medical care.


Asunto(s)
Transición a la Atención de Adultos , Adulto , Humanos , Niño , Encuestas y Cuestionarios , Personal de Salud
4.
Genet Med ; 24(2): 364-373, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-34906496

RESUMEN

PURPOSE: BRG1/BRM-associated factor (BAF) complex is a chromatin remodeling complex that plays a critical role in gene regulation. Defects in the genes encoding BAF subunits lead to BAFopathies, a group of neurodevelopmental disorders with extensive locus and phenotypic heterogeneity. METHODS: We retrospectively analyzed data from 16,243 patients referred for clinical exome sequencing (ES) with a focus on the BAF complex. We applied a genotype-first approach, combining predicted genic constraints to propose candidate BAFopathy genes. RESULTS: We identified 127 patients carrying pathogenic variants, likely pathogenic variants, or de novo variants of unknown clinical significance in 11 known BAFopathy genes. Those include 34 patients molecularly diagnosed using ES reanalysis with new gene-disease evidence (n = 21) or variant reclassifications in known BAFopathy genes (n = 13). We also identified de novo or predicted loss-of-function variants in 4 candidate BAFopathy genes, including ACTL6A, BICRA (implicated in Coffin-Siris syndrome during this study), PBRM1, and SMARCC1. CONCLUSION: We report the mutational spectrum of BAFopathies in an ES cohort. A genotype-driven and pathway-based reanalysis of ES data identified new evidence for candidate genes involved in BAFopathies. Further mechanistic and phenotypic characterization of additional patients are warranted to confirm their roles in human disease and to delineate their associated phenotypic spectrums.


Asunto(s)
Anomalías Múltiples , Deformidades Congénitas de la Mano , Micrognatismo , Anomalías Múltiples/genética , Actinas/genética , Proteínas Cromosómicas no Histona/genética , Proteínas de Unión al ADN/genética , Exoma/genética , Deformidades Congénitas de la Mano/genética , Humanos , Micrognatismo/genética , Estudios Retrospectivos
5.
Am J Med Genet A ; 188(12): 3516-3524, 2022 12.
Artículo en Inglés | MEDLINE | ID: mdl-35934918

RESUMEN

Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is caused by heterozygous or hemizygous variants in CDKL5 and is characterized by refractory epilepsy, cognitive and motor impairments, and cerebral visual impairment. CDKL5 has multiple transcripts, of which the longest transcripts, NM_003159 and NM_001037343, have been used historically in clinical laboratory testing. However, the transcript NM_001323289 is the most highly expressed in brain and contains 170 nucleotides at the 3' end of its last exon that are noncoding in other transcripts. Two truncating variants in this region have been reported in association with a CDD phenotype. To clarify the significance and range of phenotypes associated with late truncating variants in this region of the predominant transcript in the brain, we report detailed information on two individuals, updated clinical information on a third individual, and a summary of published and unpublished individuals reported in ClinVar. The two new individuals (one male and one female) each had a relatively mild clinical presentation including periods of pharmaco-responsive epilepsy, independent walking and limited purposeful communication skills. A previously reported male continued to have a severe phenotype. Overall, variants in this region demonstrate a range of clinical severity consistent with reports in CDD but with the potential for milder presentation.


Asunto(s)
Síndromes Epilépticos , Espasmos Infantiles , Masculino , Femenino , Humanos , Espasmos Infantiles/diagnóstico , Espasmos Infantiles/genética , Espasmos Infantiles/complicaciones , Síndromes Epilépticos/genética , Fenotipo , Encéfalo , Proteínas Serina-Treonina Quinasas/genética
6.
Am J Med Genet A ; 188(6): 1915-1927, 2022 06.
Artículo en Inglés | MEDLINE | ID: mdl-35266292

RESUMEN

RASopathies are a group of genetic disorders that are caused by genes that affect the canonical Ras/mitogen-activated protein kinase (MAPK) signaling pathway. Despite tremendous progress in understanding the molecular consequences of these genetic anomalies, little movement has been made in translating these findings to the clinic. This year, the seventh International RASopathies Symposium focused on expanding the research knowledge that we have gained over the years to enhance new discoveries in the field, ones that we hope can lead to effective therapeutic treatments. Indeed, for the first time, research efforts are finally being translated to the clinic, with compassionate use of Ras/MAPK pathway inhibitors for the treatment of RASopathies. This biannual meeting, organized by the RASopathies Network, brought together basic scientists, clinicians, clinician scientists, patients, advocates, and their families, as well as representatives from pharmaceutical companies and the National Institutes of Health. A history of RASopathy gene discovery, identification of new disease genes, and the latest research, both at the bench and in the clinic, were discussed.


Asunto(s)
Síndrome de Costello , Síndrome de Noonan , Síndrome de Costello/genética , Humanos , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Síndrome de Noonan/genética , Transducción de Señal , Proteínas ras/genética , Proteínas ras/metabolismo
7.
Am J Hum Genet ; 103(1): 154-162, 2018 07 05.
Artículo en Inglés | MEDLINE | ID: mdl-29961569

RESUMEN

TRAF7 is a multi-functional protein involved in diverse signaling pathways and cellular processes. The phenotypic consequence of germline TRAF7 variants remains unclear. Here we report missense variants in TRAF7 in seven unrelated individuals referred for clinical exome sequencing. The seven individuals share substantial phenotypic overlap, with developmental delay, congenital heart defects, limb and digital anomalies, and dysmorphic features emerging as key unifying features. The identified variants are de novo in six individuals and comprise four distinct missense changes, including a c.1964G>A (p.Arg655Gln) variant that is recurrent in four individuals. These variants affect evolutionarily conserved amino acids and are located in key functional domains. Gene-specific mutation rate analysis showed that the occurrence of the de novo variants in TRAF7 (p = 2.6 × 10-3) and the recurrent de novo c.1964G>A (p.Arg655Gln) variant (p = 1.9 × 10-8) in our exome cohort was unlikely to have occurred by chance. In vitro analyses of the observed TRAF7 mutations showed reduced ERK1/2 phosphorylation. Our findings suggest that missense mutations in TRAF7 are associated with a multisystem disorder and provide evidence of a role for TRAF7 in human development.


Asunto(s)
Discapacidades del Desarrollo/genética , Discapacidad Intelectual/genética , Mutación Missense/genética , Péptidos y Proteínas Asociados a Receptores de Factores de Necrosis Tumoral/genética , Adulto , Aminoácidos/genética , Niño , Preescolar , Exoma/genética , Femenino , Cardiopatías Congénitas/genética , Humanos , Lactante , Recién Nacido , Sistema de Señalización de MAP Quinasas/genética , Masculino , Anomalías Musculoesqueléticas/genética , Fenotipo
8.
J Genet Couns ; 30(4): 1181-1190, 2021 08.
Artículo en Inglés | MEDLINE | ID: mdl-33713511

RESUMEN

Rapid genomic testing is increasingly used in inpatient settings for diagnostic and treatment purposes. With the expansion of genetic testing in this setting, requests for inpatient genetics consultations have increased. There have been reports of genetic counselors working in inpatient care, though their specific roles are not well described. In this study, we characterized the roles of genetic counselors practicing in inpatient care settings in the United States and Canada. Genetic counselors were recruited via professional organization listservs to complete an online survey. The survey gathered information on participants' roles and workflow of inpatient genetics consultation services at their institution. Responses from 132 participants demonstrate that 50.4% of genetic counselors cover genetics consultations as needed or on a rotating schedule (34.6%). They practice in general pediatric (59.1%), neonatal (42.5%), cancer (28.3%), and/or prenatal (18.9%) specialties, among others. Participants reported working independently (16.1%) or with other providers (54.8%), including geneticists and other attending physicians. The workflow of genetics consultation services varies between institutions in the delivery of consults, members of the inpatient genetics consultation care team, and administrative support. Fifty percent of participants reported having no exposure to inpatients during graduate training, and 87.3% of participants reported receiving no institutional training for their inpatient role. This is the first study to describe roles of genetic counselors in inpatient care. It establishes a foundation for future research on inpatient genetic counseling and genetic counseling outcomes in inpatient services. As demand for genetics expertise in inpatient care grows, genetic counselors can be hired to serve inpatient populations alongside genetics and non-genetics providers.


Asunto(s)
Consejeros , Niño , Femenino , Asesoramiento Genético , Pruebas Genéticas , Humanos , Recién Nacido , Pacientes Internos , Embarazo , Encuestas y Cuestionarios , Estados Unidos
9.
Hum Mutat ; 41(3): 641-654, 2020 03.
Artículo en Inglés | MEDLINE | ID: mdl-31769566

RESUMEN

Visceral myopathy with abnormal intestinal and bladder peristalsis includes a clinical spectrum with megacystis-microcolon intestinal hypoperistalsis syndrome and chronic intestinal pseudo-obstruction. The vast majority of cases are caused by dominant variants in ACTG2; however, the overall genetic architecture of visceral myopathy has not been well-characterized. We ascertained 53 families, with visceral myopathy based on megacystis, functional bladder/gastrointestinal obstruction, or microcolon. A combination of targeted ACTG2 sequencing and exome sequencing was used. We report a molecular diagnostic rate of 64% (34/53), of which 97% (33/34) is attributed to ACTG2. Strikingly, missense mutations in five conserved arginine residues involving CpG dinucleotides accounted for 49% (26/53) of disease in the cohort. As a group, the ACTG2-negative cases had a more favorable clinical outcome and more restricted disease. Within the ACTG2-positive group, poor outcomes (characterized by total parenteral nutrition dependence, death, or transplantation) were invariably due to one of the arginine missense alleles. Analysis of specific residues suggests a severity spectrum of p.Arg178>p.Arg257>p.Arg40 along with other less-frequently reported sites p.Arg63 and p.Arg211. These results provide genotype-phenotype correlation for ACTG2-related disease and demonstrate the importance of arginine missense changes in visceral myopathy.


Asunto(s)
Actinas/genética , Sustitución de Aminoácidos , Arginina , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Seudoobstrucción Intestinal/diagnóstico , Seudoobstrucción Intestinal/genética , Mutación , Anomalías Múltiples/diagnóstico , Anomalías Múltiples/genética , Adulto , Colon/anomalías , Análisis Mutacional de ADN , Femenino , Genotipo , Humanos , Masculino , Técnicas de Diagnóstico Molecular , Fenotipo , Vejiga Urinaria/anomalías , Secuenciación del Exoma , Adulto Joven
10.
Am J Hum Genet ; 101(5): 833-843, 2017 Nov 02.
Artículo en Inglés | MEDLINE | ID: mdl-29100093

RESUMEN

Gorlin-Chaudhry-Moss syndrome (GCMS) is a dysmorphic syndrome characterized by coronal craniosynostosis and severe midface hypoplasia, body and facial hypertrichosis, microphthalmia, short stature, and short distal phalanges. Variable lipoatrophy and cutis laxa are the basis for a progeroid appearance. Using exome and genome sequencing, we identified the recurrent de novo mutations c.650G>A (p.Arg217His) and c.649C>T (p.Arg217Cys) in SLC25A24 in five unrelated girls diagnosed with GCMS. Two of the girls had pronounced neonatal progeroid features and were initially diagnosed with Wiedemann-Rautenstrauch syndrome. SLC25A24 encodes a mitochondrial inner membrane ATP-Mg/Pi carrier. In fibroblasts from affected individuals, the mutated SLC25A24 showed normal stability. In contrast to control cells, the probands' cells showed mitochondrial swelling, which was exacerbated upon treatment with hydrogen peroxide (H2O2). The same effect was observed after overexpression of the mutant cDNA. Under normal culture conditions, the mitochondrial membrane potential of the probands' fibroblasts was intact, whereas ATP content in the mitochondrial matrix was lower than that in control cells. However, upon H2O2 exposure, the membrane potential was significantly elevated in cells harboring the mutated SLC25A24. No reduction of mitochondrial DNA copy number was observed. These findings demonstrate that mitochondrial dysfunction with increased sensitivity to oxidative stress is due to the SLC25A24 mutations. Our results suggest that the SLC25A24 mutations induce a gain of pathological function and link mitochondrial ATP-Mg/Pi transport to the development of skeletal and connective tissue.


Asunto(s)
Anomalías Múltiples/genética , Antiportadores/genética , Proteínas de Unión al Calcio/genética , Anomalías Craneofaciales/genética , Craneosinostosis/genética , Conducto Arterioso Permeable/genética , Hipertricosis/genética , Mitocondrias/genética , Proteínas Mitocondriales/genética , Mutación/genética , Adenosina Trifosfato/genética , Adolescente , Niño , Preescolar , Cutis Laxo/genética , ADN Mitocondrial/genética , Exoma/genética , Femenino , Retardo del Crecimiento Fetal/genética , Fibroblastos/patología , Trastornos del Crecimiento , Humanos , Peróxido de Hidrógeno/farmacología , Lactante , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Potencial de la Membrana Mitocondrial/genética , Mitocondrias/efectos de los fármacos , Estrés Oxidativo/genética , Progeria/genética
11.
Am J Med Genet A ; 182(3): 597-606, 2020 03.
Artículo en Inglés | MEDLINE | ID: mdl-31825160

RESUMEN

The RASopathies are a group of genetic disorders that result from germline pathogenic variants affecting RAS-mitogen activated protein kinase (MAPK) pathway genes. RASopathies share RAS/MAPK pathway dysregulation and share phenotypic manifestations affecting numerous organ systems, causing lifelong and at times life-limiting medical complications. RASopathies may benefit from precision medicine approaches. For this reason, the Sixth International RASopathies Symposium focused on exploring precision medicine. This meeting brought together basic science researchers, clinicians, clinician scientists, patient advocates, and representatives from pharmaceutical companies and the National Institutes of Health. Novel RASopathy genes, variants, and animal models were discussed in the context of medication trials and drug development. Attempts to define and measure meaningful endpoints for treatment trials were discussed, as was drug availability to patients after trial completion.


Asunto(s)
Enfermedades Genéticas Congénitas/genética , Quinasas de Proteína Quinasa Activadas por Mitógenos/genética , Proteínas ras/genética , Enfermedades Genéticas Congénitas/patología , Mutación de Línea Germinal/genética , Humanos , Transducción de Señal/genética
12.
Prenat Diagn ; 40(10): 1246-1257, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32474937

RESUMEN

BACKGROUND: Disease severity is important when considering genes for inclusion on reproductive expanded carrier screening (ECS) panels. We applied a validated and previously published algorithm that classifies diseases into four severity categories (mild, moderate, severe, and profound) to 176 genes screened by ECS. Disease traits defining severity categories in the algorithm were then mapped to four severity-related ECS panel design criteria cited by the American College of Obstetricians and Gynecologists (ACOG). METHODS: Eight genetic counselors (GCs) and four medical geneticists (MDs) applied the severity algorithm to subsets of 176 genes. MDs and GCs then determined by group consensus how each of these disease traits mapped to ACOG severity criteria, enabling determination of the number of ACOG severity criteria met by each gene. RESULTS: Upon consensus GC and MD application of the severity algorithm, 68 (39%) genes were classified as profound, 71 (40%) as severe, 36 (20%) as moderate, and one (1%) as mild. After mapping of disease traits to ACOG severity criteria, 170 out of 176 genes (96.6%) were found to meet at least one of the four criteria, 129 genes (73.3%) met at least two, 73 genes (41.5%) met at least three, and 17 genes (9.7%) met all four. CONCLUSION: This study classified the severity of a large set of Mendelian genes by collaborative clinical expert application of a trait-based algorithm. Further, it operationalized difficult to interpret ACOG severity criteria via mapping of disease traits, thereby promoting consistency of ACOG criteria interpretation.


Asunto(s)
Anomalías Congénitas/clasificación , Anomalías Congénitas/diagnóstico , Genes del Desarrollo , Tamización de Portadores Genéticos/métodos , Asesoramiento Genético , Adolescente , Algoritmos , Niño , Preescolar , Anomalías Congénitas/genética , Anomalías Congénitas/patología , Femenino , Genes del Desarrollo/genética , Tamización de Portadores Genéticos/normas , Asesoramiento Genético/métodos , Asesoramiento Genético/normas , Enfermedades Genéticas Congénitas/clasificación , Enfermedades Genéticas Congénitas/diagnóstico , Enfermedades Genéticas Congénitas/genética , Enfermedades Genéticas Congénitas/patología , Predisposición Genética a la Enfermedad , Humanos , Lactante , Recién Nacido , Masculino , Guías de Práctica Clínica como Asunto , Embarazo , Diagnóstico Prenatal/métodos , Diagnóstico Prenatal/normas , Índice de Severidad de la Enfermedad , Adulto Joven
13.
Hum Mol Genet ; 26(24): 4937-4950, 2017 12 15.
Artículo en Inglés | MEDLINE | ID: mdl-29040572

RESUMEN

Iron-sulfur (Fe-S) clusters are ubiquitous cofactors essential to various cellular processes, including mitochondrial respiration, DNA repair, and iron homeostasis. A steadily increasing number of disorders are being associated with disrupted biogenesis of Fe-S clusters. Here, we conducted whole-exome sequencing of patients with optic atrophy and other neurological signs of mitochondriopathy and identified 17 individuals from 13 unrelated families with recessive mutations in FDXR, encoding the mitochondrial membrane-associated flavoprotein ferrodoxin reductase required for electron transport from NADPH to cytochrome P450. In vitro enzymatic assays in patient fibroblast cells showed deficient ferredoxin NADP reductase activity and mitochondrial dysfunction evidenced by low oxygen consumption rates (OCRs), complex activities, ATP production and increased reactive oxygen species (ROS). Such defects were rescued by overexpression of wild-type FDXR. Moreover, we found that mice carrying a spontaneous mutation allelic to the most common mutation found in patients displayed progressive gait abnormalities and vision loss, in addition to biochemical defects consistent with the major clinical features of the disease. Taken together, these data provide the first demonstration that germline, hypomorphic mutations in FDXR cause a novel mitochondriopathy and optic atrophy in humans.


Asunto(s)
Ferredoxinas/genética , Atrofia Óptica/genética , Sulfito Reductasa (Ferredoxina)/genética , Adolescente , Alelos , Animales , Niño , Preescolar , Transporte de Electrón , Femenino , Ferredoxinas/metabolismo , Humanos , Lactante , Hierro/metabolismo , Proteínas Hierro-Azufre/genética , Masculino , Ratones , Mitocondrias/genética , Mitocondrias/metabolismo , Membranas Mitocondriales/metabolismo , Mutagénesis , Mutación , Oxidorreductasas/genética , Oxidorreductasas/metabolismo , Linaje , Sulfito Reductasa (Ferredoxina)/metabolismo , Secuenciación del Exoma/métodos
14.
Am J Hum Genet ; 98(2): 373-81, 2016 Feb 04.
Artículo en Inglés | MEDLINE | ID: mdl-26833328

RESUMEN

Mutations in more than a hundred genes have been reported to cause X-linked recessive intellectual disability (ID) mainly in males. In contrast, the number of identified X-linked genes in which de novo mutations specifically cause ID in females is limited. Here, we report 17 females with de novo loss-of-function mutations in USP9X, encoding a highly conserved deubiquitinating enzyme. The females in our study have a specific phenotype that includes ID/developmental delay (DD), characteristic facial features, short stature, and distinct congenital malformations comprising choanal atresia, anal abnormalities, post-axial polydactyly, heart defects, hypomastia, cleft palate/bifid uvula, progressive scoliosis, and structural brain abnormalities. Four females from our cohort were identified by targeted genetic testing because their phenotype was suggestive for USP9X mutations. In several females, pigment changes along Blaschko lines and body asymmetry were observed, which is probably related to differential (escape from) X-inactivation between tissues. Expression studies on both mRNA and protein level in affected-female-derived fibroblasts showed significant reduction of USP9X level, confirming the loss-of-function effect of the identified mutations. Given that some features of affected females are also reported in known ciliopathy syndromes, we examined the role of USP9X in the primary cilium and found that endogenous USP9X localizes along the length of the ciliary axoneme, indicating that its loss of function could indeed disrupt cilium-regulated processes. Absence of dysregulated ciliary parameters in affected female-derived fibroblasts, however, points toward spatiotemporal specificity of ciliary USP9X (dys-)function.


Asunto(s)
Discapacidades del Desarrollo/genética , Discapacidad Intelectual/genética , Mutación , Ubiquitina Tiolesterasa/genética , Adolescente , Secuencia de Bases , Niño , Preescolar , Atresia de las Coanas/diagnóstico , Atresia de las Coanas/genética , Discapacidades del Desarrollo/diagnóstico , Femenino , Genes Ligados a X , Pruebas Genéticas , Humanos , Discapacidad Intelectual/diagnóstico , Datos de Secuencia Molecular , Fenotipo , Ubiquitina Tiolesterasa/metabolismo , Inactivación del Cromosoma X , Adulto Joven
15.
Am J Med Genet A ; 179(7): 1376-1382, 2019 07.
Artículo en Inglés | MEDLINE | ID: mdl-31069960

RESUMEN

The myelin regulatory factor gene (MYRF) encodes a transcription factor that is widely expressed. There is increasing evidence that heterozygous loss-of-function variants in MYRF can lead to abnormal development of the heart, genitourinary tract, diaphragm, and lungs. Here, we searched a clinical database containing the results of 12,000 exome sequencing studies. We identified three previously unreported males with putatively deleterious variants in MYRF: one with a point mutation predicted to affect splicing and two with frameshift variants. In all cases where parental DNA was available, these variants were found to have arisen de novo. The phenotypes identified in these subjects included a variety of congenital heart defects (CHD) (hypoplastic left heart syndrome, scimitar syndrome, septal defects, and valvular anomalies), genitourinary anomalies (ambiguous genitalia, hypospadias, and cryptorchidism), congenital diaphragmatic hernia, and pulmonary hypoplasia. The phenotypes seen in our subjects overlap those described in individuals diagnosed with PAGOD syndrome [MIM# 202660], a clinically defined syndrome characterized by pulmonary artery and lung hypoplasia, agonadism, omphalocele, and diaphragmatic defects that can also be associated with hypoplastic left heart and scimitar syndrome. These cases provide additional evidence that haploinsufficiency of MYRF causes a genetic syndrome whose cardinal features include CHD, urogenital anomalies, congenital diaphragmatic hernia, and pulmonary hypoplasia. We also conclude that consideration should be given to screening individuals with PAGOD for pathogenic variants in MYRF, and that individuals with MYRF deficiency who survive the neonatal period should be monitored closely for developmental delay and intellectual disability.


Asunto(s)
Haploinsuficiencia , Proteínas de la Membrana/genética , Fenotipo , Factores de Transcripción/genética , Secuencia de Aminoácidos , Femenino , Humanos , Recién Nacido , Masculino , Proteínas de la Membrana/química , Homología de Secuencia de Aminoácido , Factores de Transcripción/química
16.
Am J Med Genet C Semin Med Genet ; 178(1): 5-9, 2018 03.
Artículo en Inglés | MEDLINE | ID: mdl-29582554

RESUMEN

By enabling precise genetic diagnosis and treatment there is great potential for inexpensive, accurate, and widely accessible genomic information to transform health care and improve the general well-being of virtually every person. To maximize this potential, approaches to genetic counseling and the role of genetic counselors will need to adapt to fit changing clinical and commercial needs worldwide. This will require overcoming multiple challenges including an inadequate workforce; development and implementation of alternate models of service delivery; integration of new technologies to improve, extend, and expand services; and support for equitable education and counseling among all populations. Genetic counselors are aptly poised to take on these challenges. The result will be better informed patients and families more capable of utilizing genetic information appropriately, making autonomous decisions about their care, and modifying their approach to disease risk to actively contribute to their health. The contributors to this issue of Seminars discuss how key areas of genetic counseling need to evolve and how genetic counselors can play a role in shaping the future of precision health.


Asunto(s)
Consejeros , Asesoramiento Genético , Pruebas Genéticas , Medicina de Precisión , Pruebas Genéticas/legislación & jurisprudencia , Humanos , Neoplasias/etiología , Neoplasias/genética
17.
Am J Hum Genet ; 97(5): 691-707, 2015 Nov 05.
Artículo en Inglés | MEDLINE | ID: mdl-26544804

RESUMEN

The genomic duplication associated with Potocki-Lupski syndrome (PTLS) maps in close proximity to the duplication associated with Charcot-Marie-Tooth disease type 1A (CMT1A). PTLS is characterized by hypotonia, failure to thrive, reduced body weight, intellectual disability, and autistic features. CMT1A is a common autosomal dominant distal symmetric peripheral polyneuropathy. The key dosage-sensitive genes RAI1 and PMP22 are respectively associated with PTLS and CMT1A. Recurrent duplications accounting for the majority of subjects with these conditions are mediated by nonallelic homologous recombination between distinct low-copy repeat (LCR) substrates. The LCRs flanking a contiguous genomic interval encompassing both RAI1 and PMP22 do not share extensive homology; thus, duplications encompassing both loci are rare and potentially generated by a different mutational mechanism. We characterized genomic rearrangements that simultaneously duplicate PMP22 and RAI1, including nine potential complex genomic rearrangements, in 23 subjects by high-resolution array comparative genomic hybridization and breakpoint junction sequencing. Insertions and microhomologies were found at the breakpoint junctions, suggesting potential replicative mechanisms for rearrangement formation. At the breakpoint junctions of these nonrecurrent rearrangements, enrichment of repetitive DNA sequences was observed, indicating that they might predispose to genomic instability and rearrangement. Clinical evaluation revealed blended PTLS and CMT1A phenotypes with a potential earlier onset of neuropathy. Moreover, additional clinical findings might be observed due to the extra duplicated material included in the rearrangements. Our genomic analysis suggests replicative mechanisms as a predominant mechanism underlying PMP22-RAI1 contiguous gene duplications and provides further evidence supporting the role of complex genomic architecture in genomic instability.


Asunto(s)
Enfermedad de Charcot-Marie-Tooth/genética , Trastornos de los Cromosomas/genética , Duplicación Cromosómica/genética , Cromosomas Humanos Par 17/genética , Duplicación de Gen , Reordenamiento Génico , Proteínas de la Mielina/genética , Factores de Transcripción/genética , Anomalías Múltiples/genética , Anomalías Múltiples/patología , Enfermedad de Charcot-Marie-Tooth/patología , Niño , Preescolar , Trastornos de los Cromosomas/patología , Hibridación Genómica Comparativa , Femenino , Estudios de Seguimiento , Genoma Humano , Genómica/métodos , Humanos , Lactante , Masculino , Modelos Genéticos , Fenotipo , Pronóstico , Recombinación Genética , Transactivadores
18.
Hum Genet ; 136(4): 377-386, 2017 04.
Artículo en Inglés | MEDLINE | ID: mdl-28251352

RESUMEN

Impairment of ubiquitin-proteasome system activity involving ubiquitin ligase genes UBE3A, UBE3B, and HUWE1 and deubiquitinating enzyme genes USP7 and USP9X has been reported in patients with neurodevelopmental delays. To date, only a handful of single-nucleotide variants (SNVs) and copy-number variants (CNVs) involving TRIP12, encoding a member of the HECT domain E3 ubiquitin ligases family on chromosome 2q36.3 have been reported. Using chromosomal microarray analysis and whole-exome sequencing (WES), we have identified, respectively, five deletion CNVs and four inactivating SNVs (two frameshifts, one missense, and one splicing) in TRIP12. Seven of these variants were found to be de novo; parental studies could not be completed in two families. Quantitative PCR analyses of the splicing mutation showed a dramatically decreased level of TRIP12 mRNA in the proband compared to the family controls, indicating a loss-of-function mechanism. The shared clinical features include intellectual disability with or without autistic spectrum disorders, speech delay, and facial dysmorphism. Our findings demonstrate that E3 ubiquitin ligase TRIP12 plays an important role in nervous system development and function. The nine presented pathogenic variants further document that TRIP12 haploinsufficiency causes a childhood-onset neurodevelopmental disorder. Finally, our data enable expansion of the phenotypic spectrum of ubiquitin-proteasome dependent disorders.


Asunto(s)
Trastorno del Espectro Autista/genética , Proteínas Portadoras/genética , Facies , Haploinsuficiencia , Discapacidad Intelectual/genética , Trastornos del Desarrollo del Lenguaje/genética , Ubiquitina-Proteína Ligasas/genética , Adolescente , Trastorno del Espectro Autista/complicaciones , Niño , Preescolar , Estudios de Cohortes , Variaciones en el Número de Copia de ADN , Femenino , Humanos , Lactante , Discapacidad Intelectual/complicaciones , Trastornos del Desarrollo del Lenguaje/complicaciones , Masculino
19.
Am J Hum Genet ; 95(5): 579-83, 2014 Nov 06.
Artículo en Inglés | MEDLINE | ID: mdl-25439098

RESUMEN

5q31.3 microdeletion syndrome is characterized by neonatal hypotonia, encephalopathy with or without epilepsy, and severe developmental delay, and the minimal critical deletion interval harbors three genes. We describe 11 individuals with clinical features of 5q31.3 microdeletion syndrome and de novo mutations in PURA, encoding transcriptional activator protein Pur-α, within the critical region. These data implicate causative PURA mutations responsible for the severe neurological phenotypes observed in this syndrome.


Asunto(s)
Anomalías Múltiples/genética , Deleción Cromosómica , Cromosomas Humanos Par 5/genética , Proteínas de Unión al ADN/genética , Hipotonía Muscular/genética , Convulsiones/genética , Factores de Transcripción/genética , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Caenorhabditis elegans/genética , Mapeo Cromosómico , Humanos , Datos de Secuencia Molecular , Mutación/genética , Análisis de Secuencia de ADN , Síndrome
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