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1.
J Inherit Metab Dis ; 2024 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-38951950

RESUMEN

Leucine aminoacyl tRNA-synthetase 1 (LARS1)-deficiency (infantile liver failure syndrome type 1 (ILFS1)) has a multisystemic phenotype including fever-associated acute liver failure (ALF), chronic neurologic abnormalities, and encephalopathic episodes. In order to better characterize encephalopathic episodes and MRI changes, 35 cranial MRIs from 13 individuals with LARS1 deficiency were systematically assessed and neurological phenotype was analyzed. All individuals had developmental delay and 10/13 had seizures. Encephalopathic episodes in 8/13 were typically associated with infections, presented with seizures and reduced consciousness, mostly accompanied by hepatic dysfunction, and recovery in 17/19 episodes. Encephalopathy without hepatic dysfunction occurred in one individual after liver transplantation. On MRI, 5/7 individuals with MRI during acute encephalopathy had deep gray matter and brainstem changes. Supratentorial cortex involvement (6/13) and cerebellar watershed injury (4/13) occurred with seizures and/or encephalopathy. Abnormal brainstem contour on sagittal images (8/13), atrophy (8/13), and myelination delay (8/13) were not clearly associated with encephalopathy. The pattern of deep gray matter and brainstem changes are apparently characteristic of encephalopathy in LARS1-deficiency, differing from patterns of hepatic encephalopathy or metabolic stroke in organic acidurias and mitochondrial diseases. While the pathomechanism remains unclear, fever and energy deficit during infections might be causative; thus, sufficient glucose and protein intake along with pro-active fever management is suggested. As severe episodes were observed during influenza infections, we strongly recommend seasonal vaccination.

2.
J Genet Couns ; 33(1): 164-167, 2024 02.
Artículo en Inglés | MEDLINE | ID: mdl-38356180

RESUMEN

We introduce Entrustable Professional Activities (EPAs) as a potential framework for clinical training and assessment in genetic counseling. We discuss advantages of this approach, review how EPAs complement Practice-Based Competencies (PBCs), describe our process of generating proposed "core" EPAs, provide examples of specialty-specific EPAs, discuss the concept of entrustment in clinical training, and propose an approach to implementation.


Asunto(s)
Asesoramiento Genético , Internado y Residencia , Humanos , Educación de Postgrado en Medicina , Competencia Clínica
3.
J Genet Couns ; 2024 Mar 19.
Artículo en Inglés | MEDLINE | ID: mdl-38504135

RESUMEN

The limited literature on Asian family communication of hereditary cancer risk and cascade genetic testing for pathogenic variants (PVs) in BRCA1 and BRCA2 has reported that Asian patients have selective communication of test results and lower cascade testing rates. To better understand the factors that impact communication and cascade testing in Asian families, we conducted an in-depth qualitative study guided by the Health Belief Model. Participants with heterozygous PVs in ATM, BRCA1, BRCA2, CHEK2, or PALB2, who identified their family's origins to an Asian country, were recruited from the Stanford Cancer Genetics Research Database in October-November 2021. Utilizing a constructivist approach, we conducted sixteen semi-structured interviews around family communication and cascade genetic testing. The research team analyzed the transcript data using a reflexive thematic approach. Extensive discussions between the research team resulted in three primary themes presented in this paper: (1) the role of family health beliefs in cascade genetic testing, (2) changes in communication as a result of genetic testing, and (3) genetics providers' role in supporting family discussions on cascade genetic testing. Certain health beliefs, such as perceived susceptibility to cancer and self-efficacy to take action, were co-created by family members and these shared beliefs influenced decisions about genetic testing, family communication, and family support during the cascade genetic testing process. Participants shared strategies for how genetics providers can prepare Asian patients for more effective conversations with relatives and better address potential testing barriers by tailoring information and providing anticipatory guidance. This study represents an important contribution to the literature about cascade testing among an underrepresented group. Shared family health beliefs about genetic testing may be particularly relevant for this community and these findings can inform strategies to increase cascade genetic testing in Asian families.

4.
Genet Med ; 25(8): 100865, 2023 08.
Artículo en Inglés | MEDLINE | ID: mdl-37125633

RESUMEN

PURPOSE: The Curaçao criteria are well-established diagnostic criteria for hereditary hemorrhagic telangiectasia (HHT), but they lack details regarding a predictive presentation of epistaxis and telangiectasias. This study collects and compares data in HHT and population cohorts to inform the application of these criteria. METHODS: In-person interviews regarding epistaxis and targeted examination for telangiectases in a general population cohort (n = 204) and an HHT cohort (n = 432) were conducted. RESULTS: Frequency of epistaxis, rather than intensity or duration, was the best discriminator of HHT. A cutoff of ≥4 nosebleeds per year alone yielded a diagnostic sensitivity of 97%, and specificity of 84%. The mean number of telangiectases at the sites investigated was 0.4 in the general population cohort and 26.5 in the HHT cohort. The most distinctive sites for telangiectases in HHT were lips and palmar fingers, whereas telangiectases of the face and dorsum of the hand were comparable in both cohorts. CONCLUSION: We propose that the Curaçao criteria be modified to include the following cutoffs: (1) epistaxis frequency of ≥4 nosebleeds per year and (2) telangiectasia count of at least 2 in characteristic locations (palmar aspect of fingers, lips, and oral cavity), and that cutaneous telangiectases at other sites not be considered relevant for diagnostic purposes.


Asunto(s)
Telangiectasia Hemorrágica Hereditaria , Telangiectasia , Humanos , Telangiectasia Hemorrágica Hereditaria/complicaciones , Telangiectasia Hemorrágica Hereditaria/diagnóstico , Telangiectasia Hemorrágica Hereditaria/epidemiología , Epistaxis/epidemiología , Epistaxis/etiología , Epistaxis/diagnóstico , Curazao , Telangiectasia/diagnóstico , Telangiectasia/epidemiología , Pacientes
5.
Am J Hum Genet ; 103(6): 1009-1021, 2018 12 06.
Artículo en Inglés | MEDLINE | ID: mdl-30471716

RESUMEN

To date, mutations in 15 actin- or microtubule-associated genes have been associated with the cortical malformation lissencephaly and variable brainstem hypoplasia. During a multicenter review, we recognized a rare lissencephaly variant with a complex brainstem malformation in three unrelated children. We searched our large brain-malformation databases and found another five children with this malformation (as well as one with a less severe variant), analyzed available whole-exome or -genome sequencing data, and tested ciliogenesis in two affected individuals. The brain malformation comprised posterior predominant lissencephaly and midline crossing defects consisting of absent anterior commissure and a striking W-shaped brainstem malformation caused by small or absent pontine crossing fibers. We discovered heterozygous de novo missense variants or an in-frame deletion involving highly conserved zinc-binding residues within the GAR domain of MACF1 in the first eight subjects. We studied cilium formation and found a higher proportion of mutant cells with short cilia than of control cells with short cilia. A ninth child had similar lissencephaly but only subtle brainstem dysplasia associated with a heterozygous de novo missense variant in the spectrin repeat domain of MACF1. Thus, we report variants of the microtubule-binding GAR domain of MACF1 as the cause of a distinctive and most likely pathognomonic brain malformation. A gain-of-function or dominant-negative mechanism appears likely given that many heterozygous mutations leading to protein truncation are included in the ExAC Browser. However, three de novo variants in MACF1 have been observed in large schizophrenia cohorts.


Asunto(s)
Orientación del Axón/genética , Movimiento Celular/genética , Secuencia Conservada/genética , Proteínas de Microfilamentos/genética , Mutación/genética , Neuronas/patología , Zinc/metabolismo , Adolescente , Tronco Encefálico/patología , Niño , Preescolar , Cilios/genética , Femenino , Humanos , Lisencefalia/genética , Masculino , Microtúbulos/genética , Malformaciones del Sistema Nervioso/genética
6.
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
7.
BMC Med ; 19(1): 199, 2021 08 18.
Artículo en Inglés | MEDLINE | ID: mdl-34404389

RESUMEN

BACKGROUND: The use of proactive genetic screening for disease prevention and early detection is not yet widespread. Professional practice guidelines from the American College of Medical Genetics and Genomics (ACMG) have encouraged reporting pathogenic variants that confer personal risk for actionable monogenic hereditary disorders, but only as secondary findings from exome or genome sequencing. The Centers for Disease Control and Prevention (CDC) recognizes the potential public health impact of three Tier 1 actionable disorders. Here, we report results of a large multi-center cohort study to determine the yield and potential value of screening healthy individuals for variants associated with a broad range of actionable monogenic disorders, outside the context of secondary findings. METHODS: Eligible adults were offered a proactive genetic screening test by health care providers in a variety of clinical settings. The screening panel based on next-generation sequencing contained up to 147 genes associated with monogenic disorders within cancer, cardiovascular, and other important clinical areas. Sequence and intragenic copy number variants classified as pathogenic, likely pathogenic, pathogenic (low penetrance), or increased risk allele were considered clinically significant and reported. Results were analyzed by clinical area and severity/burden of disease using chi-square tests without Yates' correction. RESULTS: Among 10,478 unrelated adults screened, 1619 (15.5%) had results indicating personal risk for an actionable monogenic disorder. In contrast, only 3.1 to 5.2% had clinically reportable variants in genes suggested by the ACMG version 2 secondary findings list to be examined during exome or genome sequencing, and 2% had reportable variants related to CDC Tier 1 conditions. Among patients, 649 (6.2%) were positive for a genotype associated with a disease of high severity/burden, including hereditary cancer syndromes, cardiovascular disorders, or malignant hyperthermia susceptibility. CONCLUSIONS: This is one of the first real-world examples of specialists and primary care providers using genetic screening with a multi-gene panel to identify health risks in their patients. Nearly one in six individuals screened for variants associated with actionable monogenic disorders had clinically significant results. These findings provide a foundation for further studies to assess the role of genetic screening as part of regular medical care.


Asunto(s)
Pruebas Genéticas , Médicos , Adulto , Estudios de Cohortes , Exoma , Predisposición Genética a la Enfermedad , Genómica , Humanos
8.
Hum Mutat ; 41(1): 150-168, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31448840

RESUMEN

Xq22 deletions that encompass PLP1 (Xq22-PLP1-DEL) are notable for variable expressivity of neurological disease traits in females ranging from a mild late-onset form of spastic paraplegia type 2 (MIM# 312920), sometimes associated with skewed X-inactivation, to an early-onset neurological disease trait (EONDT) of severe developmental delay, intellectual disability, and behavioral abnormalities. Size and gene content of Xq22-PLP1-DEL vary and were proposed as potential molecular etiologies underlying variable expressivity in carrier females where two smallest regions of overlap (SROs) were suggested to influence disease. We ascertained a cohort of eight unrelated patients harboring Xq22-PLP1-DEL and performed high-density array comparative genomic hybridization and breakpoint-junction sequencing. Molecular characterization of Xq22-PLP1-DEL from 17 cases (eight herein and nine published) revealed an overrepresentation of breakpoints that reside within repeats (11/17, ~65%) and the clustering of ~47% of proximal breakpoints in a genomic instability hotspot with characteristic non-B DNA density. These findings implicate a potential role for genomic architecture in stimulating the formation of Xq22-PLP1-DEL. The correlation of Xq22-PLP1-DEL gene content with neurological disease trait in female cases enabled refinement of the associated SROs to a single genomic interval containing six genes. Our data support the hypothesis that genes contiguous to PLP1 contribute to EONDT.


Asunto(s)
Deleción Cromosómica , Cromosomas Humanos X , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Enfermedades del Sistema Nervioso/diagnóstico , Enfermedades del Sistema Nervioso/genética , Carácter Cuantitativo Heredable , Niño , Preescolar , Puntos de Rotura del Cromosoma , Mapeo Cromosómico , Hibridación Genómica Comparativa , Femenino , Estudios de Asociación Genética/métodos , Humanos , Masculino , Linaje , Fenotipo , Secuencias Repetitivas de Ácidos Nucleicos , Factores Sexuales , Síndrome , Inactivación del Cromosoma X
9.
Genet Med ; 22(11): 1863-1873, 2020 11.
Artículo en Inglés | MEDLINE | ID: mdl-32699352

RESUMEN

PURPOSE: Biallelic variants in LARS1, coding for the cytosolic leucyl-tRNA synthetase, cause infantile liver failure syndrome 1 (ILFS1). Since its description in 2012, there has been no systematic analysis of the clinical spectrum and genetic findings. METHODS: Individuals with biallelic variants in LARS1 were included through an international, multicenter collaboration including novel and previously published patients. Clinical variables were analyzed and functional studies were performed in patient-derived fibroblasts. RESULTS: Twenty-five individuals from 15 families were ascertained including 12 novel patients with eight previously unreported variants. The most prominent clinical findings are recurrent elevation of liver transaminases up to liver failure and encephalopathic episodes, both triggered by febrile illness. Magnetic resonance image (MRI) changes during an encephalopathic episode can be consistent with metabolic stroke. Furthermore, growth retardation, microcytic anemia, neurodevelopmental delay, muscular hypotonia, and infection-related seizures are prevalent. Aminoacylation activity is significantly decreased in all patient cells studied upon temperature elevation in vitro. CONCLUSION: ILFS1 is characterized by recurrent elevation of liver transaminases up to liver failure in conjunction with abnormalities of growth, blood, nervous system, and musculature. Encephalopathic episodes with seizures can occur independently from liver crises and may present with metabolic stroke.


Asunto(s)
Fallo Hepático , Humanos , Hipotonía Muscular , Mutación , Convulsiones
10.
Pediatr Transplant ; 23(4): e13402, 2019 06.
Artículo en Inglés | MEDLINE | ID: mdl-31012250

RESUMEN

There is a limited supply of organs for all those who need them for survival. Thus, careful decisions must be made about who is listed for transplant. Studies show that manifesting genetic disease can impact listing eligibility. What has not yet been studied is the impact genetic risks for future disease have on a patient's chance to be listed. Surveys were emailed to 163 pediatric liver, heart, and kidney transplant programs across the United States to elicit views and experiences of key clinicians regarding each program's use of genetic risks (ie, predispositions, positive predictive testing) in listing decisions. Response rate was 42%. Sixty-four percent of programs have required genetic testing for specific indications prior to listing decisions. Sixteen percent have required it without specific indications, suggesting that genetic testing may be used to screen candidates. Six percent have chosen not to list patients with secondary findings or family histories of genetic conditions. In hypothetical scenarios, programs consider cancer predispositions and adult-onset neurological conditions to be relative contraindications to listing (61%, 17%, and 8% depending on scenario), and some consider them absolute contraindications (5% and 3% depending on scenario). Only 3% of programs have formal policies for these scenarios, but all consult genetic specialists at least "sometimes" for results interpretation. Our study reveals that pediatric transplant programs are using future onset genetic risks in listing decisions. As genetic testing is increasingly adopted into pediatric medicine, further study is needed to prevent possible inappropriate use of genetic information from impacting listing eligibility.


Asunto(s)
Trasplante de Órganos/métodos , Trasplante de Órganos/normas , Selección de Paciente , Obtención de Tejidos y Órganos/métodos , Obtención de Tejidos y Órganos/normas , Listas de Espera , Adulto , Neoplasias de la Mama/genética , Niño , Toma de Decisiones , Progresión de la Enfermedad , Exoma , Salud de la Familia , Femenino , Genes BRCA1 , Genes p53 , Predisposición Genética a la Enfermedad , Pruebas Genéticas , Variación Genética , Trasplante de Corazón/métodos , Trasplante de Corazón/normas , Humanos , Enfermedad de Huntington/genética , Internet , Trasplante de Riñón/métodos , Trasplante de Riñón/normas , Trasplante de Hígado/métodos , Trasplante de Hígado/normas , Masculino , Neoplasias Ováricas/genética , Pediatría , Factores de Riesgo , Encuestas y Cuestionarios , Estados Unidos , Secuenciación Completa del Genoma
11.
J Genet Couns ; 28(4): 878-886, 2019 08.
Artículo en Inglés | MEDLINE | ID: mdl-31050105

RESUMEN

Variants of uncertain significance (VUSs) are often disclosed to patients despite ambiguous association with disease risk and lack of clinical actionability. It is important to understand how patients understand a VUS result, but few studies have assessed this. Our qualitative study explored patient recall, reaction to, and interpretation of a VUS in the context of multigene panels. We conducted 11 semi-structured phone interviews with adults who had a VUS identified on multigene panel testing in a hereditary oncology clinic, with questions focusing on the VUS result, personal and family history, and motivations for and expectations of genetic testing. Transcripts were coded iteratively, using both deductive and inductive codes. Overall, participants usually recalled that they had a VUS, despite variation in the vocabulary used. Participants responded both emotionally and intellectually to receiving information about having a VUS, which was often a result of their expectations and motivations prior to testing. Overall, participants understood the lack of clinical significance of a VUS, yet often interpreted the etiologic significance of a VUS within the context of the personal and family history. Our study provides insight into a process by which patients translate uncertain genetic testing results into a construct that fits within their current belief framework and which may be facilitated by a genetic counselor.


Asunto(s)
Pruebas Genéticas/métodos , Adulto , Anciano , Femenino , Predisposición Genética a la Enfermedad , Humanos , Masculino , Anamnesis , Persona de Mediana Edad , Incertidumbre
12.
J Genet Couns ; 28(2): 466-476, 2019 04.
Artículo en Inglés | MEDLINE | ID: mdl-30706981

RESUMEN

With the wide adoption of next-generation sequencing (NGS)-based genetic tests, genetic counselors require increased familiarity with NGS technology, variant interpretation concepts, and variant assessment tools. The use of exome and genome sequencing in clinical care has expanded the reach and diversity of genetic testing. Regardless of the setting where genetic counselors are performing variant interpretation or reporting, most of them have learned these skills from colleagues, while on the job. Though traditional, lecture-based learning around these topics is important, there has been growing need for the inclusion of case-based, experiential training of genomics and variant interpretation for genetic counseling students, with the goal of creating a strong foundation in variant interpretation for new genetic counselors, regardless of what area of practice they enter. To address this need, we established a genomics and variant interpretation rotation for Stanford's genetic counseling training program. In response to changes in the genomics landscape, this has now evolved into three unique rotation experiences, each focused on variant interpretation in the context of various genomic settings, including clinical laboratory, research laboratory, and healthy genomic analysis studies. Here, we describe the goals and learning objectives that we have developed for these variant interpretation rotations, and illustrate how these concepts are applied in practice.


Asunto(s)
Consejeros/educación , Curriculum , Asesoramiento Genético , Pruebas Genéticas , Genómica/educación , Adulto , Humanos , Desarrollo de Programa , Universidades
13.
Circulation ; 136(11): 1037-1048, 2017 Sep 12.
Artículo en Inglés | MEDLINE | ID: mdl-28687708

RESUMEN

BACKGROUND: Most arteriovenous malformations (AVMs) are localized and occur sporadically. However, they also can be multifocal in autosomal-dominant disorders, such as hereditary hemorrhagic telangiectasia and capillary malformation (CM)-AVM. Previously, we identified RASA1 mutations in 50% of patients with CM-AVM. Herein we studied non-RASA1 patients to further elucidate the pathogenicity of CMs and AVMs. METHODS: We conducted a genome-wide linkage study on a CM-AVM family. Whole-exome sequencing was also performed on 9 unrelated CM-AVM families. We identified a candidate gene and screened it in a large series of patients. The influence of several missense variants on protein function was also studied in vitro. RESULTS: We found evidence for linkage in 2 loci. Whole-exome sequencing data unraveled 4 distinct damaging variants in EPHB4 in 5 families that cosegregated with CM-AVM. Overall, screening of EPHB4 detected 47 distinct mutations in 54 index patients: 27 led to a premature stop codon or splice-site alteration, suggesting loss of function. The other 20 are nonsynonymous variants that result in amino acid substitutions. In vitro expression of several mutations confirmed loss of function of EPHB4. The clinical features included multifocal CMs, telangiectasias, and AVMs. CONCLUSIONS: We found EPHB4 mutations in patients with multifocal CMs associated with AVMs. The phenotype, CM-AVM2, mimics RASA1-related CM-AVM1 and also hereditary hemorrhagic telangiectasia. RASA1-encoded p120RASGAP is a direct effector of EPHB4. Our data highlight the pathogenetic importance of this interaction and indicts EPHB4-RAS-ERK signaling pathway as a major cause for AVMs.


Asunto(s)
Malformaciones Arteriovenosas/diagnóstico , Malformaciones Arteriovenosas/genética , Capilares/anomalías , Mutación de Línea Germinal/genética , Sistema de Señalización de MAP Quinasas/fisiología , Mancha Vino de Oporto/diagnóstico , Mancha Vino de Oporto/genética , Receptor EphB4/genética , Proteína Activadora de GTPasa p120/genética , Bases de Datos Genéticas , Femenino , Estudio de Asociación del Genoma Completo/métodos , Humanos , Masculino , Linaje
14.
Am J Med Genet A ; 176(12): 2887-2891, 2018 12.
Artículo en Inglés | MEDLINE | ID: mdl-30450842

RESUMEN

Stickler syndrome is a connective tissue disorder characterized by hearing loss, ocular anomalies, palatal defects, and skeletal abnormalities. The autosomal dominant form is the most common, but autosomal recessive forms have also been described. We report the second case of autosomal recessive Stickler syndrome due to homozygosity for a loss of function mutation in COL9A3, which encodes the α3 chain of type IX procollagen. The clinical features were similar to the previously described COL9A3 Stickler syndrome family, including moderate to severe sensorineural hearing loss, high myopia, and both tibial and femoral bowing at birth. Radiographs demonstrated abnormal capital femoral epiphyses and mild irregularities of the vertebral endplates. This case further establishes the phenotype associated with mutations in this gene. We suggest that loss of the α3 chain of type IX collagen results in a Stickler syndrome phenotype similar to that of the other autosomal recessive forms caused by mutations in genes encoding the α1 and α2 chains of type IX collagen.


Asunto(s)
Artritis/diagnóstico , Artritis/genética , Colágeno Tipo IX/genética , Enfermedades del Tejido Conjuntivo/diagnóstico , Enfermedades del Tejido Conjuntivo/genética , Genes Recesivos , Pérdida Auditiva Sensorineural/diagnóstico , Pérdida Auditiva Sensorineural/genética , Mutación , Desprendimiento de Retina/diagnóstico , Desprendimiento de Retina/genética , Niño , Análisis Mutacional de ADN , Homocigoto , Humanos , Recién Nacido , Fenotipo , Radiografía , Secuenciación del Exoma
15.
J Med Genet ; 54(9): 613-623, 2017 09.
Artículo en Inglés | MEDLINE | ID: mdl-28735298

RESUMEN

BACKGROUND: Mutations in forkhead box protein P1 (FOXP1) cause intellectual disability (ID) and specific language impairment (SLI), with or without autistic features (MIM: 613670). Despite multiple case reports no specific phenotype emerged so far. METHODS: We correlate clinical and molecular data of 25 novel and 23 previously reported patients with FOXP1 defects. We evaluated FOXP1 activity by an in vitro luciferase model and assessed protein stability in vitro by western blotting. RESULTS: Patients show ID, SLI, neuromotor delay (NMD) and recurrent facial features including a high broad forehead, bent downslanting palpebral fissures, ptosis and/or blepharophimosis and a bulbous nasal tip. Behavioural problems and autistic features are common. Brain, cardiac and urogenital malformations can be associated. More severe ID and NMD, sensorineural hearing loss and feeding difficulties are more common in patients with interstitial 3p deletions (14 patients) versus patients with monogenic FOXP1 defects (34 patients). Mutations result in impaired transcriptional repression and/or reduced protein stability. CONCLUSIONS: FOXP1-related ID syndrome is a recognisable entity with a wide clinical spectrum and frequent systemic involvement. Our data will be helpful to evaluate genotype-phenotype correlations when interpreting next-generation sequencing data obtained in patients with ID and/or SLI and will guide clinical management.


Asunto(s)
Factores de Transcripción Forkhead/genética , Discapacidad Intelectual/genética , Proteínas Represoras/genética , Trastorno del Espectro Autista/genética , Cara/anomalías , Femenino , Factores de Transcripción Forkhead/química , Factores de Transcripción Forkhead/metabolismo , Humanos , Trastornos del Lenguaje/genética , Masculino , Trastornos de la Destreza Motora/genética , Mutación , Mutación Missense , Trastornos del Neurodesarrollo/genética , Fenotipo , Estabilidad Proteica , Proteínas Represoras/química , Proteínas Represoras/metabolismo , Síndrome , Transcripción Genética
16.
J Genet Couns ; 2018 Sep 15.
Artículo en Inglés | MEDLINE | ID: mdl-30220053

RESUMEN

Individuals with hypertrophic cardiomyopathy (HCM) and long QT syndrome (LQTS) are advised to avoid certain forms of exercise to reduce their risk of sudden death. Cardiovascular genetic counselors facilitate both adaptation to, and decision-making about, these exercise recommendations. This study describes decision-making and experiences of active adults who exercise above physicians' recommendations. Purposive sampling was used to select adults with HCM and LQTS who self-identified as exercising above recommendations. Semi-structured interviews explored participants' decision-making and the psychological impact of exercise recommendations. Fifteen individuals were interviewed (HCM: 10; LQTS: 5; mean age: 40). Transcripts were coded and analyzed for underlying themes. Despite exercising above recommendations, nearly all participants made some modifications to their prior exercise regimen. Often these decisions changed over time, underscoring the importance of shared decision-making conversations beyond the initial evaluation. The importance of exercise was frequently cited as a reason for continued exercise, as were perceptions of sudden death risk as low, acceptable, or modifiable. Many participants reported that family and friends supported their exercise decisions, with a minority having family or friends that expressed significant reservations. Genetic counselors, cardiologists, and nurses can use these data to inform their counseling regarding exercise recommendations.

18.
Am J Med Genet A ; 170(3): 670-5, 2016 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-26842493

RESUMEN

We report on 19 individuals with a recurrent de novo c.607C>T mutation in PACS1. This specific mutation gives rise to a recognizable intellectual disability syndrome. There is a distinctive facial appearance (19/19), characterized by full and arched eyebrows, hypertelorism with downslanting palpebral fissures, long eye lashes, ptosis, low set and simple ears, bulbous nasal tip, wide mouth with downturned corners and a thin upper lip with an unusual "wavy" profile, flat philtrum, and diastema of the teeth. Intellectual disability, ranging from mild to moderate, was present in all. Hypotonia is common in infancy (8/19). Seizures are frequent (12/19) and respond well to anticonvulsive medication. Structural malformations are common, including heart (10/19), brain (12/16), eye (10/19), kidney (3/19), and cryptorchidism (6/12 males). Feeding dysfunction is presenting in infancy with failure to thrive (5/19), gastroesophageal reflux (6/19), and gastrostomy tube placement (4/19). There is persistence of oral motor dysfunction. We provide suggestions for clinical work-up and management and hope that the present study will facilitate clinical recognition of further cases.


Asunto(s)
Anomalías Múltiples/genética , Discapacidad Intelectual/genética , Mutación Puntual , Convulsiones/genética , Proteínas de Transporte Vesicular/genética , Anomalías Múltiples/diagnóstico , Anomalías Múltiples/tratamiento farmacológico , Anomalías Múltiples/patología , Adolescente , Anticonvulsivantes/uso terapéutico , Niño , Preescolar , Facies , Insuficiencia de Crecimiento/diagnóstico , Insuficiencia de Crecimiento/tratamiento farmacológico , Insuficiencia de Crecimiento/genética , Insuficiencia de Crecimiento/patología , Femenino , Expresión Génica , Humanos , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/tratamiento farmacológico , Discapacidad Intelectual/patología , Masculino , Hipotonía Muscular/diagnóstico , Hipotonía Muscular/tratamiento farmacológico , Hipotonía Muscular/genética , Hipotonía Muscular/patología , Convulsiones/diagnóstico , Convulsiones/tratamiento farmacológico , Convulsiones/patología , Índice de Severidad de la Enfermedad , Síndrome , Adulto Joven
19.
J Genet Couns ; 25(6): 1188-1197, 2016 12.
Artículo en Inglés | MEDLINE | ID: mdl-27103420

RESUMEN

Huntington disease (HD) is an autosomal dominant, progressive neurodegenerative disorder for which there is no cure. Predictive testing for HD is available to asymptomatic at-risk individuals. Approximately half of the population undergoing predictive testing for HD consists of young adults (≤35 years old). Finishing one's education, starting a career, engaging in romantic relationships and becoming a parent are key milestones of young adulthood. We conducted a qualitative study to explore how testing gene-positive for HD influences young adults' attainment of these milestones, and to identify major challenges that pre-symptomatic young adults face to aid the development of targeted genetic counseling. Results of our study demonstrate that 1) knowing one's gene-positive status results in an urgency to reach milestones and positively changes young adults' approach to life; 2) testing positive influences young adults' education and career choices, romantic relationships, and family planning; 3) young adults desire flexible and tailored genetic counseling to address needs and concerns unique to this population. Findings of this study contribute to the understanding of the impact of predictive testing for HD on young adults, and highlight issues unique to this population that call for further research, intervention and advocacy.


Asunto(s)
Asesoramiento Genético , Enfermedad de Huntington/psicología , Pacientes/psicología , Guías de Práctica Clínica como Asunto , Adulto , Selección de Profesión , Femenino , Humanos , Enfermedad de Huntington/genética , Masculino , Motivación , Padres/psicología , Investigación Cualitativa , Adulto Joven
20.
J Clin Transl Sci ; 6(1): e35, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35433035

RESUMEN

Introduction: This research examined the perspective of the Huntington's disease (HD) community regarding the use of predictive biomarkers as endpoints for regulatory approval of therapeutics to prevent or delay the onset of clinical HD in asymptomatic mutation carriers. Methods: An online, choice-based conjoint survey was shared with HD community members including untested at-risk individuals, presymptomatic mutation carriers, and symptomatic individuals. Across 15 scenarios, participants chose among two proposed therapies with differing degrees of biomarker improvement and side effects or a third option of no treatment. Results: Two hundred and thirty-eight responses were received. Attributes reflecting biomarker efficacy (e.g., prevention of brain atrophy on magnetic resonance imaging, reduced mutant huntingtin, or reduced inflammation biomarkers) had 3- to 7-fold greater importance than attributes representing side effects (e.g., increased risk of heart disease, cancer, and stroke over 20 years) and were more influential in directing choice of treatments. Reduction in mutant huntingtin protein was the most valued attribute overall. Multinomial logit model simulations based on survey responses demonstrated high interest among respondents (87-99% of the population) for drugs that might prevent or delay HD solely based upon biomarker evidence, even at the risk of serious side effects. Conclusion: These results indicate a strong desire among members of the HD community for preventive therapeutics and a willingness to accept significant side effects, even before the drug has been shown to definitively delay disease onset if the drug improves biomarker evidence of HD progression. Preferences of the HD community should inform regulatory policies for approving preventive therapies.

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