RESUMEN
Deletion 1p36 (del1p36) syndrome is the most common human disorder resulting from a terminal autosomal deletion. This condition is molecularly and clinically heterogeneous. Deletions involving two non-overlapping regions, known as the distal (telomeric) and proximal (centromeric) critical regions, are sufficient to cause the majority of the recurrent clinical features, although with different facial features and dysmorphisms. SPEN encodes a transcriptional repressor commonly deleted in proximal del1p36 syndrome and is located centromeric to the proximal 1p36 critical region. Here, we used clinical data from 34 individuals with truncating variants in SPEN to define a neurodevelopmental disorder presenting with features that overlap considerably with those of proximal del1p36 syndrome. The clinical profile of this disease includes developmental delay/intellectual disability, autism spectrum disorder, anxiety, aggressive behavior, attention deficit disorder, hypotonia, brain and spine anomalies, congenital heart defects, high/narrow palate, facial dysmorphisms, and obesity/increased BMI, especially in females. SPEN also emerges as a relevant gene for del1p36 syndrome by co-expression analyses. Finally, we show that haploinsufficiency of SPEN is associated with a distinctive DNA methylation episignature of the X chromosome in affected females, providing further evidence of a specific contribution of the protein to the epigenetic control of this chromosome, and a paradigm of an X chromosome-specific episignature that classifies syndromic traits. We conclude that SPEN is required for multiple developmental processes and SPEN haploinsufficiency is a major contributor to a disorder associated with deletions centromeric to the previously established 1p36 critical regions.
Asunto(s)
Trastornos de los Cromosomas/genética , Cromosomas Humanos Par 1/genética , Cromosomas Humanos X/genética , Proteínas de Unión al ADN/genética , Proteínas de Unión al ARN/genética , Adolescente , Trastorno del Espectro Autista/genética , Trastorno del Espectro Autista/patología , Niño , Preescolar , Deleción Cromosómica , Trastornos de los Cromosomas/fisiopatología , Metilación de ADN/genética , Epigénesis Genética/genética , Femenino , Haploinsuficiencia/genética , Humanos , Discapacidad Intelectual/genética , Discapacidad Intelectual/fisiopatología , Masculino , Trastornos del Neurodesarrollo/genética , Trastornos del Neurodesarrollo/fisiopatología , Fenotipo , Adulto JovenRESUMEN
PURPOSE: RAS genes (HRAS, KRAS, and NRAS) are commonly found to be mutated in cancers, and activating RAS variants are also found in disorders of somatic mosaicism (DoSM). A survey of the mutational spectrum of RAS variants in DoSM has not been performed. METHODS: A total of 938 individuals with suspected DoSM underwent high-sensitivity clinical next-generation sequencing-based testing. We investigated the mutational spectrum and genotype-phenotype associations of mosaic RAS variants. RESULTS: In this article, we present a series of individuals with DoSM with RAS variants. Classic hotspots, including Gly12, Gly13, and Gln61 constituted the majority of RAS variants observed in DoSM. Furthermore, we present 12 individuals with HRAS and KRAS in-frame duplication/insertion (dup/ins) variants in the switch II domain. Among the 18.3% individuals with RAS in-frame dup/ins variants, clinical findings were mainly associated with vascular malformations. Hotspots were associated with a broad phenotypic spectrum, including vascular tumors, vascular malformations, nevoid proliferations, segmental overgrowth, digital anomalies, and combinations of these. The median age at testing was higher and the variant allelic fraction was lower in individuals with in-frame dup/ins variants than those in individuals with mosaic RAS hotspots. CONCLUSION: Our work provides insight into the allelic and clinical heterogeneity of mosaic RAS variants in nonmalignant conditions.
Asunto(s)
Mosaicismo , Malformaciones Vasculares , Humanos , Proteínas Proto-Oncogénicas p21(ras)/genética , Mutación , Alelos , Malformaciones Vasculares/genéticaRESUMEN
SMARCC2 (BAF170) is one of the invariable core subunits of the ATP-dependent chromatin remodeling BAF (BRG1-associated factor) complex and plays a crucial role in embryogenesis and corticogenesis. Pathogenic variants in genes encoding other components of the BAF complex have been associated with intellectual disability syndromes. Despite its significant biological role, variants in SMARCC2 have not been directly associated with human disease previously. Using whole-exome sequencing and a web-based gene-matching program, we identified 15 individuals with variable degrees of neurodevelopmental delay and growth retardation harboring one of 13 heterozygous variants in SMARCC2, most of them novel and proven de novo. The clinical presentation overlaps with intellectual disability syndromes associated with other BAF subunits, such as Coffin-Siris and Nicolaides-Baraitser syndromes and includes prominent speech impairment, hypotonia, feeding difficulties, behavioral abnormalities, and dysmorphic features such as hypertrichosis, thick eyebrows, thin upper lip vermilion, and upturned nose. Nine out of the fifteen individuals harbor variants in the highly conserved SMARCC2 DNA-interacting domains (SANT and SWIRM) and present with a more severe phenotype. Two of these individuals present cardiac abnormalities. Transcriptomic analysis of fibroblasts from affected individuals highlights a group of differentially expressed genes with possible roles in regulation of neuronal development and function, namely H19, SCRG1, RELN, and CACNB4. Our findings suggest a novel SMARCC2-related syndrome that overlaps with neurodevelopmental disorders associated with variants in BAF-complex subunits.
Asunto(s)
Discapacidades del Desarrollo/complicaciones , Discapacidades del Desarrollo/genética , Discapacidad Intelectual/complicaciones , Discapacidad Intelectual/genética , Mutación , Factores de Transcripción/genética , Anomalías Múltiples/genética , Adolescente , Niño , Preescolar , Proteínas de Unión al ADN , Cara/anomalías , Femenino , Deformidades Congénitas de la Mano/genética , Humanos , Masculino , Micrognatismo/genética , Cuello/anomalías , Proteína Reelina , SíndromeRESUMEN
Proteins anchored to the cell surface via glycosylphosphatidylinositol (GPI) play various key roles in the human body, particularly in development and neurogenesis. As such, many developmental disorders are caused by mutations in genes involved in the GPI biosynthesis and remodeling pathway. We describe ten unrelated families with bi-allelic mutations in PIGB, a gene that encodes phosphatidylinositol glycan class B, which transfers the third mannose to the GPI. Ten different PIGB variants were found in these individuals. Flow cytometric analysis of blood cells and fibroblasts from the affected individuals showed decreased cell surface presence of GPI-anchored proteins. Most of the affected individuals have global developmental and/or intellectual delay, all had seizures, two had polymicrogyria, and four had a peripheral neuropathy. Eight children passed away before four years old. Two of them had a clinical diagnosis of DOORS syndrome (deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures), a condition that includes sensorineural deafness, shortened terminal phalanges with small finger and toenails, intellectual disability, and seizures; this condition overlaps with the severe phenotypes associated with inherited GPI deficiency. Most individuals tested showed elevated alkaline phosphatase, which is a characteristic of the inherited GPI deficiency but not DOORS syndrome. It is notable that two severely affected individuals showed 2-oxoglutaric aciduria, which can be seen in DOORS syndrome, suggesting that severe cases of inherited GPI deficiency and DOORS syndrome might share some molecular pathway disruptions.
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Anomalías Craneofaciales/etiología , Glicosilfosfatidilinositoles/biosíntesis , Glicosilfosfatidilinositoles/deficiencia , Deformidades Congénitas de la Mano/etiología , Pérdida Auditiva Sensorineural/etiología , Discapacidad Intelectual/etiología , Manosiltransferasas/genética , Enfermedades Metabólicas/etiología , Mutación , Uñas Malformadas/etiología , Enfermedades del Sistema Nervioso Periférico/etiología , Convulsiones/patología , Adulto , Niño , Preescolar , Anomalías Craneofaciales/patología , Femenino , Glicosilfosfatidilinositoles/genética , Deformidades Congénitas de la Mano/patología , Pérdida Auditiva Sensorineural/patología , Humanos , Lactante , Recién Nacido , Discapacidad Intelectual/patología , Masculino , Enfermedades Metabólicas/patología , Uñas Malformadas/patología , Linaje , Enfermedades del Sistema Nervioso Periférico/patología , Convulsiones/genética , Índice de Severidad de la Enfermedad , Adulto JovenRESUMEN
We identified individuals with variations in ACTL6B, a component of the chromatin remodeling machinery including the BAF complex. Ten individuals harbored bi-allelic mutations and presented with global developmental delay, epileptic encephalopathy, and spasticity, and ten individuals with de novo heterozygous mutations displayed intellectual disability, ambulation deficits, severe language impairment, hypotonia, Rett-like stereotypies, and minor facial dysmorphisms (wide mouth, diastema, bulbous nose). Nine of these ten unrelated individuals had the identical de novo c.1027G>A (p.Gly343Arg) mutation. Human-derived neurons were generated that recaptured ACTL6B expression patterns in development from progenitor cell to post-mitotic neuron, validating the use of this model. Engineered knock-out of ACTL6B in wild-type human neurons resulted in profound deficits in dendrite development, a result recapitulated in two individuals with different bi-allelic mutations, and reversed on clonal genetic repair or exogenous expression of ACTL6B. Whole-transcriptome analyses and whole-genomic profiling of the BAF complex in wild-type and bi-allelic mutant ACTL6B neural progenitor cells and neurons revealed increased genomic binding of the BAF complex in ACTL6B mutants, with corresponding transcriptional changes in several genes including TPPP and FSCN1, suggesting that altered regulation of some cytoskeletal genes contribute to altered dendrite development. Assessment of bi-alleic and heterozygous ACTL6B mutations on an ACTL6B knock-out human background demonstrated that bi-allelic mutations mimic engineered deletion deficits while heterozygous mutations do not, suggesting that the former are loss of function and the latter are gain of function. These results reveal a role for ACTL6B in neurodevelopment and implicate another component of chromatin remodeling machinery in brain disease.
Asunto(s)
Actinas/genética , Proteínas Cromosómicas no Histona/genética , Proteínas de Unión al ADN/genética , Dendritas/patología , Epilepsia/etiología , Células Madre Pluripotentes Inducidas/patología , Mutación , Trastornos del Neurodesarrollo/etiología , Neuronas/patología , Adulto , Niño , Preescolar , Cromatina/genética , Cromatina/metabolismo , Dendritas/metabolismo , Epilepsia/patología , Femenino , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Lactante , Masculino , Trastornos del Neurodesarrollo/patología , Neuronas/metabolismo , Adulto JovenRESUMEN
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 RetrospectivosRESUMEN
Nemaline Myopathy (NM) is a disorder of skeletal muscles caused by mutations in sarcomere proteins and characterized by accumulation of microscopic rod or thread-like structures (nemaline bodies) in skeletal muscles. Patients diagnosed with both NM and infantile cardiomyopathy are very rare. A male infant presented, within the first few hours of life, with severe dilated cardiomyopathy, biventricular dysfunction and left ventricular noncompaction. A muscle biopsy on the 8th day of life from the right sternocleidomastoid muscle identified nemaline rods. Whole exome sequencing identified a c.1288 delT (homozygous pathogenic variant) in the CAP2 gene (NM_006366), yielding a CAP2 protein (NP_006357.1) with a p.C430fs. Both parents were heterozygous for the same variant but have no history of heart or muscle disease. Analysis of patient derived fibroblasts and cardiomyocytes derived from induced pluripotent stem cells confirmed the p.C430fs mutation (pathogenic variant), which appears to cause loss of both CAP2 protein and mRNA. The CAP2 gene encodes cyclase associated protein 2, an actin monomer binding and filament depolymerizing protein and CAP2 knockout mice develop severe dilated cardiomyopathy and muscle weakness. The patient underwent a heart transplant at 1 year of age. Heart tissue explanted at that time also showed nemaline rods and additionally disintegration of the myofibrillar structure. Other extra cardiac concerns include mild hypotonia, atrophic and widened scarring. This is the first description of a patient presenting with nemaline myopathy associated with a pathogenic variant of CAP2.
Asunto(s)
Cardiomiopatía Dilatada , Miopatías Nemalínicas , Proteínas Adaptadoras Transductoras de Señales/genética , Cardiomiopatía Dilatada/complicaciones , Cardiomiopatía Dilatada/diagnóstico , Cardiomiopatía Dilatada/genética , Homocigoto , Humanos , Recién Nacido , Masculino , Proteínas de la Membrana/genética , Músculo Esquelético/patología , Mutación , Miopatías Nemalínicas/diagnóstico , Miopatías Nemalínicas/genética , Miopatías Nemalínicas/patologíaRESUMEN
Children or adults with mosaic trisomy 12 diagnosed postnatally are extremely rare. Only a small number of patients with this mosaicism have been reported in the literature. The clinical manifestation of mosaic trisomy 12 is variable, ranging from mild developmental delay to severe congenital anomaly and neonatal death. The trisomy 12 cells are not usually able to be detected by phytohemagglutinin stimulated peripheral blood chromosome analysis. The variability of phenotypes and the limited number of patients with this anomaly pose a challenge to predict the clinical outcomes. In this study, we present the phenotypes and laboratory findings in four patients and review the 11 previously reported patients with mosaic trisomy 12 diagnosed postnatally, as well as 11 patients with mosaic trisomy 12 diagnosed prenatally. The findings of this study provide useful information for laboratory diagnosis and clinical management of these patients.
Asunto(s)
Anomalías Múltiples/diagnóstico , Trastornos de los Cromosomas/diagnóstico , Anomalías Congénitas/diagnóstico , Discapacidades del Desarrollo/diagnóstico , Trisomía/genética , Anomalías Múltiples/genética , Niño , Preescolar , Trastornos de los Cromosomas/genética , Cromosomas Humanos Par 12/genética , Anomalías Congénitas/genética , Discapacidades del Desarrollo/genética , Femenino , Pruebas Genéticas , Humanos , Lactante , Recién Nacido , Masculino , Mosaicismo , Fenotipo , Diagnóstico PrenatalRESUMEN
Hand-Foot-Genital syndrome is a rare autosomal dominant condition characterized by distal limb anomalies and urogenital malformations. This disorder is associated with loss-of-function mutations in the HOXA13 gene. HOXA13 plays an important role in the development of distal limbs and lower genitourinary tract of the fetus. We report a novel familial 589 kb deletion in the 7p15.2 region identified in a male toddler and his mother. The proband had severe penoscrotal hypospadias, mild skeletal anomalies of the hands and feet, cardiac, renal, and gastrointestinal anomalies. His mother had a bicornuate uterus, cervical incompetence, and minor anomalies of her hands and feet. This family was found to have the smallest reported deletion of 7p15.2 to date, and presented with features typical of Hand-Foot-Genital syndrome in the mother, but much more severe phenotype in her son. This deletion included the entire HOXA cluster in addition to the SKAP2 and EVX1 genes. An RT-PCR analysis was performed to determine the expression of the HOXA genes in the proband and to explore a parent-of-origin effect. Our expression studies did not support the hypothesis of an imprinted status of the HOXA2, HOXA3, HOXA5, and HOXA11 genes in peripheral blood. To our knowledge, this is the first familial 7p15.2 deletion. This family raises possibility for sexual dimorphism as a mechanism for phenotypic variability in patients with the HOXA gene cluster deletions. © 2016 Wiley Periodicals, Inc.
Asunto(s)
Anomalías Múltiples/diagnóstico , Anomalías Múltiples/genética , Deformidades Congénitas del Pie/diagnóstico , Deformidades Congénitas del Pie/genética , Estudios de Asociación Genética , Deformidades Congénitas de la Mano/diagnóstico , Deformidades Congénitas de la Mano/genética , Proteínas de Homeodominio/genética , Fenotipo , Eliminación de Secuencia , Anomalías Urogenitales/diagnóstico , Anomalías Urogenitales/genética , Cromosomas Humanos Par 7 , Hibridación Genómica Comparativa , Humanos , Lactante , Masculino , Análisis de Secuencia por Matrices de Oligonucleótidos , Linaje , Polimorfismo de Nucleótido SimpleRESUMEN
Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is a lethal lung developmental disorder caused by heterozygous point mutations or genomic deletion copy-number variants (CNVs) of FOXF1 or its upstream enhancer involving fetal lung-expressed long noncoding RNA genes LINC01081 and LINC01082. Using custom-designed array comparative genomic hybridization, Sanger sequencing, whole exome sequencing (WES), and bioinformatic analyses, we studied 22 new unrelated families (20 postnatal and two prenatal) with clinically diagnosed ACDMPV. We describe novel deletion CNVs at the FOXF1 locus in 13 unrelated ACDMPV patients. Together with the previously reported cases, all 31 genomic deletions in 16q24.1, pathogenic for ACDMPV, for which parental origin was determined, arose de novo with 30 of them occurring on the maternally inherited chromosome 16, strongly implicating genomic imprinting of the FOXF1 locus in human lungs. Surprisingly, we have also identified four ACDMPV families with the pathogenic variants in the FOXF1 locus that arose on paternal chromosome 16. Interestingly, a combination of the severe cardiac defects, including hypoplastic left heart, and single umbilical artery were observed only in children with deletion CNVs involving FOXF1 and its upstream enhancer. Our data demonstrate that genomic imprinting at 16q24.1 plays an important role in variable ACDMPV manifestation likely through long-range regulation of FOXF1 expression, and may be also responsible for key phenotypic features of maternal uniparental disomy 16. Moreover, in one family, WES revealed a de novo missense variant in ESRP1, potentially implicating FGF signaling in the etiology of ACDMPV.
Asunto(s)
Genoma Humano , Impresión Genómica , Síndrome de Circulación Fetal Persistente/patología , Alveolos Pulmonares/anomalías , Venas Pulmonares/patología , Cromosomas Humanos Par 16/genética , Hibridación Genómica Comparativa , Femenino , Factores de Transcripción Forkhead/genética , Genes Letales , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Recién Nacido , Masculino , Linaje , Síndrome de Circulación Fetal Persistente/genética , Alveolos Pulmonares/patología , Eliminación de SecuenciaRESUMEN
INTRODUCTION: The complex structure of the chromosome 2q12.3-q13 region provides a high chance of recombination events between various low copy repeats (LCRs). Copy number variants (CNV) in this region are present in both healthy populations and individuals affected with developmental delay, autism and congenital anomalies. Variable expressivity, reduced penetrance and limited characterization of the affected genes have complicated the classification of the CNVs clinical significance. METHODS: Chromosomal microarray analysis data were reviewed for 10 298 patients with neurodevelopmental disorders referred to the UPMC Medical Genetics and Genomics Laboratories. A genotype-phenotype correlation was performed among the patients harboring the 2q12.3-q13 CNVs with overlapping genomic intervals. RESULTS: We identified 17 (1 in ~600) individuals with rare CNVs in the 2q12.3-q13 region, including nine patients with deletions, seven individuals with duplications and one patient who had both a deletion and a duplication. Likely pathogenic CNVs with the breakpoints between LCRs encompassing the potential dosage-sensitive genes BCL2L11, BUB1, FBLN7 and TMEM87B were the most common. CNVs were also observed between LCRs surrounding the RANBP2 and LIMS1 genes. CONCLUSION: Our study provides evidence for pathogenic CNV hotspots within the chromosome 2q12.3-q13 region. We suggest CNV classification based on the affected interval and the involvement of potential dosage-sensitive genes in these patients.
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Variaciones en el Número de Copia de ADN , Trastornos del Neurodesarrollo , Cromosomas , Variaciones en el Número de Copia de ADN/genética , Estudios de Asociación Genética , Genómica , Humanos , Trastornos del Neurodesarrollo/genéticaRESUMEN
Autism spectrum disorder (ASD) represents a group of neurodevelopmental phenotypes with a strong genetic component. An excess of likely gene-disruptive (LGD) mutations in GIGYF1 was implicated in ASD. Here, we report that GIGYF1 is the second-most mutated gene among known ASD high-confidence risk genes. We investigated the inheritance of 46 GIGYF1 LGD variants, including the highly recurrent mutation c.333del:p.L111Rfs*234. Inherited GIGYF1 heterozygous LGD variants were 1.8 times more common than de novo mutations. Among individuals with ASD, cognitive impairments were less likely in those with GIGYF1 LGD variants relative to those with other high-confidence gene mutations. Using a Gigyf1 conditional KO mouse model, we showed that haploinsufficiency in the developing brain led to social impairments without significant cognitive impairments. In contrast, homozygous mice showed more severe social disability as well as cognitive impairments. Gigyf1 deficiency in mice led to a reduction in the number of upper-layer cortical neurons, accompanied by a decrease in proliferation and increase in differentiation of neural progenitor cells. We showed that GIGYF1 regulated the recycling of IGF-1R to the cell surface. KO of GIGYF1 led to a decreased level of IGF-1R on the cell surface, disrupting the IGF-1R/ERK signaling pathway. In summary, our findings show that GIGYF1 is a regulator of IGF-1R recycling. Haploinsufficiency of GIGYF1 was associated with autistic behavior, likely through interference with IGF-1R/ERK signaling pathway.
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Trastorno del Espectro Autista , Trastorno Autístico , Animales , Trastorno del Espectro Autista/genética , Trastorno del Espectro Autista/metabolismo , Trastorno Autístico/genética , Trastorno Autístico/metabolismo , Ratones , Neuronas/metabolismo , Fenotipo , Transducción de SeñalRESUMEN
BACKGROUND: CTNNB1 (MIM 116806) encodes beta-catenin, an adherens junction protein that supports the integrity between layers of epithelial tissue and mediates intercellular signaling. Recently, various heterozygous germline variants in CTNNB1 have been associated with human disease, including neurodevelopmental disorder with spastic diplegia and visual defects (MIM 615075) as well as isolated familial exudative vitreoretinopathy without developmental delays or other organ system involvement (MIM 617572). From over 40 previously reported patients with CTNNB1-related neurodevelopmental disorder, many have had ocular anomalies including strabismus, hyperopia, and astigmatism. More recently, multiple reports indicate that these abnormalities are associated with the presence of vitreoretinopathy. METHODS: We gathered a cohort of three patients with CTNNB1-related neurodevelopmental disorder, recruited from both our own clinic and referred from outside providers. We then searched for a clinical database comprised of over 12,000 exome sequencing studies to identify and recruit four additional patients. RESULTS: Here, we report seven new cases of CTNNB1-related neurodevelopmental disorder, all harboring de novo variants, six of which were previously unreported. All patients but one presented with a spectrum of ocular abnormalities and one patient, who was found to carry a missense variant in CTNNB1, had notable vitreoretinopathy. CONCLUSIONS: Our findings suggest ophthalmologic screening should be performed in all patients with CTNNB1 variants.
Asunto(s)
Discapacidades del Desarrollo/genética , Vitreorretinopatías Exudativas Familiares/genética , beta Catenina/genética , Niño , Preescolar , Discapacidades del Desarrollo/patología , Vitreorretinopatías Exudativas Familiares/patología , Femenino , Humanos , Lactante , Masculino , Mutación Missense , Fenotipo , Retina/patologíaRESUMEN
BACKGROUND: Pathogenic variants in DYRK1A are associated with DYRK1A-related intellectual disability syndrome (DIDS). Common features of this diagnosis include microcephaly, intellectual disability, speech impairment, and distinct facial features. Reported ocular features include deep-set eyes, myopia, and strabismus. We present a case of DYRK1A-related intellectual disability syndrome with ocular findings of albinism and explore the possible pathogenesis of this previously unreported manifestation. MATERIALS AND METHODS: This is a single, retrospective case report of a child with DIDS who underwent an ophthalmic exam including detailed visual electrophysiology. Results: A 21-month-old female with microcephaly, failure to thrive, language delay, cleft palate, and cardiac defects had an ophthalmic exam showing myopia, strabismus, a hypopigmented fundus and crossed asymmetry on visual evoked potential (VEP), consistent with ocular findings of albinism. Whole exome sequencing identified a pathogenic DYRK1A variant; no albinism gene variants were reported. Her constellation of features is consistent with a diagnosis of DYRK1A-related intellectual disability syndrome; however, ocular features of albinism have not previously been reported in this condition. CONCLUSIONS: This is, to the best of our knowledge, the first report of ocular findings of albinism in a case of DYRK1A-related intellectual disability syndrome. We propose that ocular albinism is a novel ocular phenotype of DYRK1A-related disease. Ophthalmic exams in patients with this diagnosis should include thorough evaluation for ocular albinism, including VEPs.
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Albinismo/patología , Haploinsuficiencia , Discapacidad Intelectual/patología , Proteínas Serina-Treonina Quinasas/genética , Proteínas Tirosina Quinasas/genética , Albinismo/complicaciones , Albinismo/genética , Potenciales Evocados Visuales , Femenino , Humanos , Lactante , Discapacidad Intelectual/complicaciones , Discapacidad Intelectual/genética , Estudios Retrospectivos , Síndrome , Quinasas DyrKRESUMEN
Reticular dysgenesis is an autosomal recessive form of severe combined immunodeficiency (SCID) that usually manifests in newborns. It is a unique example of an immune deficiency that is linked to dysfunctional mitochondrial energy metabolism and caused by adenylate kinase 2 (AK2) deficiency. It is characterized by an early differentiation arrest in the myeloid lineage, impaired lymphoid maturation, and sensorineural hearing loss. In this study, a novel AK2 homozygous mutation, c.622 T > C [p.Ser208Pro], was identified in an Old Order Amish patient through whole exome sequencing. Functional studies showed that the patient's cells have no detectable AK2 protein, as well as low oxygen consumption rate (OCR), extracellular acidification rate (ECAR) and proton production rate (PPR). An increased production of reactive oxygen species, mitochondrial membrane permeability, and mitochondrial mass, and decreased ATP production, were also observed. The results confirm the pathogenicity of the AK2 mutation and demonstrate that reticular dysgenesis should be considered in Amish individuals presenting with immune deficiency. We also describe other pathophysiological aspects of AK2 deficiency not previously reported.
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Adenilato Quinasa/genética , Leucopenia/diagnóstico , Mitocondrias/metabolismo , Inmunodeficiencia Combinada Grave/diagnóstico , Adenilato Quinasa/deficiencia , Médula Ósea/patología , Permeabilidad de la Membrana Celular , Preescolar , Metabolismo Energético , Fibroblastos/citología , Fibroblastos/metabolismo , Homocigoto , Humanos , Leucopenia/genética , Masculino , Membranas Mitocondriales/metabolismo , Consumo de Oxígeno , Linaje , Polimorfismo de Nucleótido Simple , Especies Reactivas de Oxígeno/metabolismo , Inmunodeficiencia Combinada Grave/genética , Secuenciación del ExomaRESUMEN
PURPOSE: In this ongoing national case series, we document 25 new genetic testing cases in which tests were recommended, ordered, interpreted, or used incorrectly. METHODS: An invitation to submit cases of adverse events in genetic testing was issued to the general National Society of Genetic Counselors Listserv, the National Society of Genetic Counselors Cancer Special Interest Group members, private genetic counselor laboratory groups, and via social media platforms (i.e., Facebook, Twitter, LinkedIn). Examples highlighted in the invitation included errors in ordering, counseling, and/or interpretation of genetic testing and did not limit submissions to cases involving genetic testing for hereditary cancer predisposition. Clinical documentation, including pedigree, was requested. Twenty-six cases were accepted, and a thematic analysis was performed. Submitters were asked to approve the representation of their cases before manuscript submission. RESULTS: All submitted cases took place in the United States and were from cancer, pediatric, preconception, and general adult settings and involved both medical-grade and direct-to-consumer genetic testing with raw data analysis. In 8 cases, providers ordered the wrong genetic test. In 2 cases, multiple errors were made when genetic testing was ordered. In 3 cases, patients received incorrect information from providers because genetic test results were misinterpreted or because of limitations in the provider's knowledge of genetics. In 3 cases, pathogenic genetic variants identified were incorrectly assumed to completely explain the suspicious family histories of cancer. In 2 cases, patients received inadequate or no information with respect to genetic test results. In 2 cases, result interpretation/documentation by the testing laboratories was erroneous. In 2 cases, genetic counselors reinterpreted the results of people who had undergone direct-to-consumer genetic testing and/or clarifying medical-grade testing was ordered. DISCUSSION: As genetic testing continues to become more common and complex, it is clear that we must ensure that appropriate testing is ordered and that results are interpreted and used correctly. Access to certified genetic counselors continues to be an issue for some because of workforce limitations. Potential solutions involve action on multiple fronts: new genetic counseling delivery models, expanding the genetic counseling workforce, improving genetics and genomics education of nongenetics health care professionals, addressing health care policy barriers, and more. Genetic counselors have also positioned themselves in new roles to help patients and consumers as well as health care providers, systems, and payers adapt to new genetic testing technologies and models. The work to be done is significant, but so are the consequences of errors in genetic testing.
Asunto(s)
Pruebas Genéticas/normas , Errores Diagnósticos , Asesoramiento Genético/métodos , Asesoramiento Genético/normas , Pruebas Genéticas/métodos , Humanos , Errores Médicos , Uso Excesivo de los Servicios de Salud , Estados UnidosRESUMEN
BACKGROUND: Neurodevelopmental disorders are impairments of brain function that affect emotion, learning, and memory. Copy number variations of contactin genes (CNTNs), including CNTN3, CNTN4, CNTN5, and CNTN6, have been suggested to be associated with these disorders. However, phenotypes have been reported in only a handful of patients with copy number variations involving CNTNs. METHODS: From January 2009 to January 2013, 3724 patients ascertained through the University of Pittsburgh Medical Center were referred to our laboratory for clinical array comparative genomic hybridization testing. We screened this cohort of patients to identify individuals with the 3p26.3 copy number variations involving the CNTN6 gene, and then retrospectively reviewed the clinical information and family history of these patients to determine the association between the 3p26.3 copy number variations and neurodevelopmental disorders. RESULTS: Fourteen of the 3724 patients had 3p26.3 copy number variations involving the CNTN6 gene. Thirteen of the 14 patients with these CNTN6 copy number variations presented with various neurodevelopmental disorders including developmental delay, autistic spectrum disorders, seizures and attention deficit hyperactivity disorder. Family history was available for 13 of the 14 patients. Twelve of the thirteen families have multiple members with neurodevelopmental and neuropsychiatric disorders including attention deficit hyperactivity disorder, seizures, autism spectrum disorder, intellectual disability, schizophrenia, depression, anxiety, learning disability, and bipolar disorder. CONCLUSIONS: Our findings suggest that deletion or duplication of the CNTN6 gene is associated with a wide spectrum of neurodevelopmental behavioral disorders.