RESUMEN
PURPOSE: Several clinical phenotypes including fetal hydrops, central conducting lymphatic anomaly or capillary malformations with arteriovenous malformations 2 (CM-AVM2) have been associated with EPHB4 (Ephrin type B receptor 4) variants, demanding new approaches for deciphering pathogenesis of novel variants of uncertain significance (VUS) identified in EPHB4, and for the identification of differentiated disease mechanisms at the molecular level. METHODS: Ten index cases with various phenotypes, either fetal hydrops, CM-AVM2, or peripheral lower limb lymphedema, whose distinct clinical phenotypes are described in detail in this study, presented with a variant in EPHB4. In vitro functional studies were performed to confirm pathogenicity. RESULTS: Pathogenicity was demonstrated for six of the seven novel EPHB4 VUS investigated. A heterogeneity of molecular disease mechanisms was identified, from loss of protein production or aberrant subcellular localization to total reduction of the phosphorylation capability of the receptor. There was some phenotype-genotype correlation; however, previously unreported intrafamilial overlapping phenotypes such as lymphatic-related fetal hydrops (LRFH) and CM-AVM2 in the same family were observed. CONCLUSION: This study highlights the usefulness of protein expression and subcellular localization studies to predict EPHB4 variant pathogenesis. Our accurate clinical phenotyping expands our interpretation of the Janus-faced spectrum of EPHB4-related disorders, introducing the discovery of cases with overlapping phenotypes.
Asunto(s)
Hidropesía Fetal , Receptor EphB4 , Estudios de Asociación Genética , Humanos , Fenotipo , Fosforilación , Receptor EphB4/genéticaRESUMEN
Direct-to-consumer genetic testing came on the scene 2 decades ago as a means for allowing consumers to access their genetic information without the involvement of a physician or genetic counselor. Results are delivered directly to the consumer, often leading to misinterpretation and needless medical interventions or false reassurance. Increasingly, we are seeing these patients in our genetics clinics for test interpretation, management guidance and confirmatory genetic testing.
Asunto(s)
Pruebas Dirigidas al Consumidor , Pruebas Genéticas , Asesoramiento Genético , Estudio de Asociación del Genoma Completo , Humanos , Médicos , Polimorfismo de Nucleótido Simple/genéticaRESUMEN
1p36 deletion syndrome is a well-described condition with a recognizable phenotype, including cognitive impairment, seizures, and structural brain anomalies such as periventricular leukomalacia (PVL). In a large series of these individuals by Battaglia et al., "birth history was notable in 50% of the cases for varying degrees of perinatal distress." Given the potential for perinatal distress, seizures and PVL, we questioned if this disorder has clinical overlap with hypoxic ischemic encephalopathy (HIE). We reviewed the medical records of 69 individuals with 1p36 deletion to clarify the perinatal phenotype of this disorder and determine if there is evidence of perinatal distress and/or hypoxic injury. Our data provides evidence that these babies have signs of perinatal distress. The majority (59% term; 75% preterm) needed resuscitation and approximately 18% had cardiac arrest. Most had abnormal brain imaging (84% term; 73% preterm) with abnormal white matter findings in over half of patients. PVL or suggestion of "hypoxic insult" was present in 18% of term and 45% of preterm patients. In conclusion, individuals with 1p36 deletion have evidence of perinatal distress, white matter changes, and seizures, which can mimic HIE but are likely related to their underlying chromosome disorder.
Asunto(s)
Trastornos de los Cromosomas/diagnóstico , Trastornos de los Cromosomas/genética , Hipoxia-Isquemia Encefálica/diagnóstico , Fenotipo , Distrés Psicológico , Deleción Cromosómica , Cromosomas Humanos Par 1/genética , Diagnóstico Diferencial , Femenino , Humanos , Recién Nacido , Masculino , EmbarazoRESUMEN
We present a case of a newborn female with multiple anomalies demonstrating that the causes of imprinting disorders rely not only on the parent-of-origin of the chromosomal aberrations, but also the scope of genes contained in the imprinted region. The newborn female presented with prenatal polyhydramnios, neonatal respiratory distress, distal contractures, abdominal hernia, bell-shaped thorax, and abnormal ribs. The neonate required mechanical ventilation due to apnea, underwent surgery for laryngomalacia, and showed development delay by age 11 months. Chromosomal microarray analysis identified a single copy number loss in chromosome region 14q32.2q32.31, containing genes that are differentially expressed based on parent-of-origin. Microarray analysis also confirmed the identical deletion in the patient's mother, who was reported to be normal. Additional molecular analyses determined the exact size and breakpoints of the deletion as well as methylation states in both the patient and her mother. The maternally transmitted deletion was responsible for Kagami-Ogata syndrome in the patient.
Asunto(s)
Anomalías Múltiples/genética , Secuencia de Bases , Cromosomas Humanos Par 14/genética , Eliminación de Secuencia , Anomalías Múltiples/patología , Femenino , Humanos , SíndromeRESUMEN
The proteins encoded by TELO2, TTI1, and TTI2 interact to form the TTT complex, a co-chaperone for maturation of the phosphatidylinositol 3-kinase-related protein kinases (PIKKs). Here we report six affected individuals from four families with intellectual disability (ID) and neurological and other congenital abnormalities associated with compound heterozygous variants in TELO2. Although their fibroblasts showed reduced steady-state levels of TELO2 and the other components of the TTT complex, PIKK functions were normal in cellular assays. Our results suggest that these TELO2 missense variants result in loss of function, perturb TTT complex stability, and cause an autosomal-recessive syndromic form of ID.
Asunto(s)
Discapacidad Intelectual/etiología , Chaperonas Moleculares/genética , Proteínas Serina-Treonina Quinasas/genética , Proteínas de Unión a Telómeros/genética , Adolescente , Proteínas Portadoras/genética , Niño , Femenino , Humanos , Péptidos y Proteínas de Señalización Intracelular , Masculino , Linaje , Fosfatidilinositol 3-Quinasas/genéticaRESUMEN
Array comparative genomic hybridization (aCGH) is a powerful genetic tool that has enabled the identification of novel imbalances in individuals with intellectual disability (ID), autistic disorders and congenital malformations. Here we report a 'genotype first' approach using aCGH on 13 unrelated patients with 19p13.3 submicroscopic rearrangement (11 deletions and 2 duplications) and review cases in the literature and in public databases. Shared phenotypic features suggest that these patients represent an interstitial microdeletion/microduplication syndrome at 19p13.3. Common features consist of abnormal head circumference in most patients (macrocephaly with the deletions and microcephaly with the duplications), ID with developmental delay (DD), hypotonia, speech delay and common dysmorphic features. The phenotype is associated with at least a ~0.113 Mb critical region harboring three strong candidate genes probably associated with DD, ID, speech delay and other dysmorphic features: MAP2K2, ZBTB7A and PIAS4, an E3 ubiquitin ligase involved in the ubiquitin signaling pathways, which we hypothesize for the first time to be associated with head size in humans.
Asunto(s)
Deleción Cromosómica , Duplicación Cromosómica , Cromosomas Humanos Par 19/genética , Discapacidades del Desarrollo/genética , Megalencefalia/genética , Microcefalia/genética , Proteínas Inhibidoras de STAT Activados/genética , Niño , Preescolar , Proteínas de Unión al ADN/genética , Discapacidades del Desarrollo/patología , Femenino , Humanos , Lactante , MAP Quinasa Quinasa 2/genética , Masculino , Megalencefalia/patología , Microcefalia/patología , Proteínas de Unión a Poli-ADP-Ribosa , Síndrome , Factores de Transcripción/genéticaRESUMEN
Chromosome 17p13.3 is a gene rich region that when deleted is associated with the well-known Miller-Dieker syndrome. A recently described duplication syndrome involving this region has been associated with intellectual impairment, autism and occasional brain MRI abnormalities. We report 34 additional patients from 21 families to further delineate the clinical, neurological, behavioral, and brain imaging findings. We found a highly diverse phenotype with inter- and intrafamilial variability, especially in cognitive development. The most specific phenotype occurred in individuals with large duplications that include both the YWHAE and LIS1 genes. These patients had a relatively distinct facial phenotype and frequent structural brain abnormalities involving the corpus callosum, cerebellar vermis, and cranial base. Autism spectrum disorders were seen in a third of duplication probands, most commonly in those with duplications of YWHAE and flanking genes such as CRK. The typical neurobehavioral phenotype was usually seen in those with the larger duplications. We did not confirm the association of early overgrowth with involvement of YWHAE and CRK, or growth failure with duplications of LIS1. Older patients were often overweight. Three variant phenotypes included cleft lip/palate (CLP), split hand/foot with long bone deficiency (SHFLD), and a connective tissue phenotype resembling Marfan syndrome. The duplications in patients with clefts appear to disrupt ABR, while the SHFLD phenotype was associated with duplication of BHLHA9 as noted in two recent reports. The connective tissue phenotype did not have a convincing critical region. Our experience with this large cohort expands knowledge of this diverse duplication syndrome.
Asunto(s)
1-Alquil-2-acetilglicerofosfocolina Esterasa/genética , Proteínas 14-3-3/genética , Encéfalo/anomalías , Trastornos de la Conducta Infantil/patología , Trastornos Generalizados del Desarrollo Infantil/patología , Cromosomas Humanos Par 17/genética , Duplicación de Gen , Proteínas Asociadas a Microtúbulos/genética , Adolescente , Adulto , Encéfalo/patología , Niño , Trastornos de la Conducta Infantil/genética , Trastornos Generalizados del Desarrollo Infantil/genética , Preescolar , Femenino , Humanos , Lactante , Masculino , FenotipoRESUMEN
Deletions at 2p16.3 involving exons of NRXN1 are associated with susceptibility for autism and schizophrenia, and similar deletions have been identified in individuals with developmental delay and dysmorphic features. We have identified 34 probands with exonic NRXN1 deletions following referral for clinical microarray-based comparative genomic hybridization. To more firmly establish the full phenotypic spectrum associated with exonic NRXN1 deletions, we report the clinical features of 27 individuals with NRXN1 deletions, who represent 23 of these 34 families. The frequency of exonic NRXN1 deletions among our postnatally diagnosed patients (0.11%) is significantly higher than the frequency among reported controls (0.02%; P = 6.08 × 10(-7) ), supporting a role for these deletions in the development of abnormal phenotypes. Generally, most individuals with NRXN1 exonic deletions have developmental delay (particularly speech), abnormal behaviors, and mild dysmorphic features. In our cohort, autism spectrum disorders were diagnosed in 43% (10/23), and 16% (4/25) had epilepsy. The presence of NRXN1 deletions in normal parents and siblings suggests reduced penetrance and/or variable expressivity, which may be influenced by genetic, environmental, and/or stochastic factors. The pathogenicity of these deletions may also be affected by the location of the deletion within the gene. Counseling should appropriately represent this spectrum of possibilities when discussing recurrence risks or expectations for a child found to have a deletion in NRXN1.
Asunto(s)
Moléculas de Adhesión Celular Neuronal/genética , Eliminación de Gen , Proteínas del Tejido Nervioso/genética , Anomalías Múltiples/diagnóstico , Anomalías Múltiples/genética , Adolescente , Adulto , Trastorno Autístico/genética , Proteínas de Unión al Calcio , Niño , Preescolar , Hibridación Genómica Comparativa , Discapacidades del Desarrollo/genética , Exones , Facies , Femenino , Interacción Gen-Ambiente , Estudio de Asociación del Genoma Completo , Humanos , Lactante , Discapacidad Intelectual/genética , Masculino , Persona de Mediana Edad , Moléculas de Adhesión de Célula Nerviosa , Penetrancia , Fenotipo , Esquizofrenia/genética , Adulto JovenRESUMEN
SOX5 encodes a transcription factor involved in the regulation of chondrogenesis and the development of the nervous system. Despite its important developmental roles, SOX5 disruption has yet to be associated with human disease. We report one individual with a reciprocal translocation breakpoint within SOX5, eight individuals with intragenic SOX5 deletions (four are apparently de novo and one inherited from an affected parent), and seven individuals with larger 12p12 deletions encompassing SOX5. Common features in these subjects include prominent speech delay, intellectual disability, behavior abnormalities, and dysmorphic features. The phenotypic impact of the deletions may depend on the location of the deletion and, consequently, which of the three major SOX5 protein isoforms are affected. One intragenic deletion, involving only untranslated exons, was present in a more mildly affected subject, was inherited from a healthy parent and grandparent, and is similar to a deletion found in a control cohort. Therefore, some intragenic SOX5 deletions may have minimal phenotypic effect. Based on the location of the deletions in the subjects compared to the controls, the de novo nature of most of these deletions, and the phenotypic similarities among cases, SOX5 appears to be a dosage-sensitive, developmentally important gene.
Asunto(s)
Trastorno Dismórfico Corporal/genética , Discapacidades del Desarrollo/genética , Haploinsuficiencia , Trastornos del Desarrollo del Lenguaje/genética , Trastornos Mentales/genética , Factores de Transcripción SOXD/genética , Adolescente , Adulto , Estudios de Casos y Controles , Niño , Preescolar , Cromosomas Humanos Par 12 , Femenino , Humanos , MasculinoRESUMEN
We report 24 unrelated individuals with deletions and 17 additional cases with duplications at 10q11.21q21.1 identified by chromosomal microarray analysis. The rearrangements range in size from 0.3 to 12 Mb. Nineteen of the deletions and eight duplications are flanked by large, directly oriented segmental duplications of >98% sequence identity, suggesting that nonallelic homologous recombination (NAHR) caused these genomic rearrangements. Nine individuals with deletions and five with duplications have additional copy number changes. Detailed clinical evaluation of 20 patients with deletions revealed variable clinical features, with developmental delay (DD) and/or intellectual disability (ID) as the only features common to a majority of individuals. We suggest that some of the other features present in more than one patient with deletion, including hypotonia, sleep apnea, chronic constipation, gastroesophageal and vesicoureteral refluxes, epilepsy, ataxia, dysphagia, nystagmus, and ptosis may result from deletion of the CHAT gene, encoding choline acetyltransferase, and the SLC18A3 gene, mapping in the first intron of CHAT and encoding vesicular acetylcholine transporter. The phenotypic diversity and presence of the deletion in apparently normal carrier parents suggest that subjects carrying 10q11.21q11.23 deletions may exhibit variable phenotypic expressivity and incomplete penetrance influenced by additional genetic and nongenetic modifiers.
Asunto(s)
Anomalías Múltiples/genética , Aberraciones Cromosómicas , Factores de Crecimiento Nervioso/genética , Duplicaciones Segmentarias en el Genoma/genética , Eliminación de Secuencia , Proteínas de Transporte Vesicular de Acetilcolina/genética , Niño , Preescolar , Mapeo Cromosómico , Cromosomas Humanos Par 10 , Variaciones en el Número de Copia de ADN , Discapacidades del Desarrollo/complicaciones , Discapacidades del Desarrollo/genética , Femenino , Variación Genética , Recombinación Homóloga , Humanos , Hibridación Fluorescente in Situ , Lactante , Discapacidad Intelectual/complicaciones , Discapacidad Intelectual/genética , Masculino , Análisis de Secuencia por Matrices de Oligonucleótidos , PenetranciaRESUMEN
The effects of missense changes and small in-frame deletions and insertions on protein function are not easy to predict, and the identification of such variants in individuals at risk of a genetic disease can complicate genetic counselling. One option is to perform functional tests to assess whether the variants affect protein function. We have used this strategy to characterize variants identified in the TSC1 and TSC2 genes in individuals with, or suspected of having, Tuberous Sclerosis Complex (TSC). Here we present an overview of our functional studies on 45 TSC1 and 107 TSC2 variants. Using a standardized protocol we classified 16 TSC1 variants and 70 TSC2 variants as pathogenic. In addition we identified eight putative splice site mutations (five TSC1 and three TSC2). The remaining 24 TSC1 and 34 TSC2 variants were classified as probably neutral.