scholarly journals Genomic diagnosis for children with intellectual disability and/or developmental delay

2016 ◽  
Author(s):  
Kevin M. Bowling ◽  
Michelle L. Thompson ◽  
Michelle D. Amaral ◽  
Candice R. Finnila ◽  
Susan M. Hiatt ◽  
...  
Keyword(s):  
Neurological Disease ◽  
Large Scale ◽  
De Novo ◽  
Pathogenic Variant ◽  
Research Progress ◽  
Degree Relative ◽  
Identification Rate ◽  
Pathogenic Variants ◽  
First Choice ◽  
Uncertain Significance

ABSTRACTBackgroundDevelopmental disabilities have diverse genetic causes that must be identified to facilitate precise diagnoses. We describe genomic data from 371 affected individuals, 309 of which were sequenced as proband-parent trios.MethodsWhole exome sequences (WES) were generated for 365 individuals (127 affected) and whole genome sequences (WGS) were generated for 612 individuals (244 affected).ResultsPathogenic or likely pathogenic variants were found in 100 individuals (27%), with variants of uncertain significance in an additional 42 (11.3%). We found that a family history of neurological disease, especially the presence of an affected 1st degree relative, reduces the pathogenic/likely pathogenic variant identification rate, reflecting both the disease relevance and ease of interpretation of de novo variants. We also found that improvements to genetic knowledge facilitated interpretation changes in many cases. Through systematic reanalyses we have thus far reclassified 15 variants, with 11.3% of families who initially were found to harbor a VUS, and 4.7% of families with a negative result, eventually found to harbor a pathogenic or likely pathogenic variant. To further such progress, the data described here are being shared through ClinVar, GeneMatcher, and dbGAP.ConclusionOur data strongly support the value of large-scale sequencing, especially WGS within proband-parent trios, as both an effective first-choice diagnostic tool and means to advance clinical and research progress related to pediatric neurological disease.

scholarly journals A Novel Missense Variant in the Gene PPP2R5D Causes a Rare Neurodevelopmental Disorder with Increased Phenotype

2021 ◽  
Vol 2021 ◽  
pp. 1-7
Author(s):  
Lulu Yan ◽  
Ru Shen ◽  
Zongfu Cao ◽  
Chunxiao Han ◽  
Yuxin Zhang ◽  
...  
Keyword(s):  
De Novo ◽  
Genetic Disorder ◽  
Neurodevelopmental Disorder ◽  
Three Dimensional ◽  
Missense Variant ◽  
Pathogenic Variant ◽  
Dimensional Structure ◽  
Chinese Family ◽  
Speech Impairment ◽  
Pathogenic Variants

PPP2R5D-related neurodevelopmental disorder, which is mainly caused by de novo missense variants in the PPP2R5D gene, is a rare autosomal dominant genetic disorder with about 100 patients and a total of thirteen pathogenic variants known to exist globally so far. Here, we present a 24-month-old Chinese boy with developmental delay and other common clinical characteristics of PPP2R5D-related neurodevelopmental disorder including hypotonia, macrocephaly, intellectual disability, speech impairment, and behavioral abnormality. Trio-whole exome sequencing (WES) and Sanger sequencing were performed to identify the causal gene variant. The pathogenicity of the variant was evaluated using bioinformatics tools. We identified a novel pathogenic variant in the PPP2R5D gene (c.620G>T, p.Trp207Leu). The variant is located in the variant hotspot region of this gene and is predicted to cause PPP2R5D protein dysfunction due to an increase in local hydrophobicity and unstable three-dimensional structure. We report a novel pathogenic variant of PPP2R5D associated with PPP2R5D-related neurodevelopmental disorder from a Chinese family. Our findings expanded the phenotypic and mutational spectrum of PPP2R5D-related neurodevelopmental disorder.

Rapidly Progressive Multisutural Craniosynostosis in a Patient With Jackson-Weiss Syndrome and a De Novo FGFR2 Pathogenic Variant

2019 ◽  
Vol 56 (10) ◽  
pp. 1386-1392
Author(s):  
Karel-Bart Celie ◽  
Melissa Yuan ◽  
Christopher Cunniff ◽  
Jarrod Bogue ◽  
Caitlin Hoffman ◽  
...  
Keyword(s):  
Clinical Outcomes ◽  
Early Treatment ◽  
Clinical Presentation ◽  
De Novo ◽  
Pathogenic Variant ◽  
Medical Complications ◽  
3 Dimensional ◽  
Constitutive Activation ◽  
Pathogenic Variants ◽  
Dimensional Modeling

Little is currently known about the mechanisms by which pathogenic variants of FGFR2 produce changes in the FGFR protein and influence the clinical presentation of affected individuals. We report on a patient with a de novo pathogenic variant of FGFR2 and a phenotype consistent with Jackson-Weiss syndrome who presented with delayed, rapidly progressive multisutural craniosynostosis and associated medical complications. Using 3-dimensional modeling of the FGFR protein, we provide evidence that this variant resulted in abnormal dimerization and constitutive activation of FGFR, leading to the Jackson-Weiss phenotype. Knowledge regarding the correlation between genotype and phenotype of persons with FGFR2-related craniosynostosis has the potential to allow for anticipation of medical complications, institution of early treatment, and improved clinical outcomes.

scholarly journals Coffin-Lowry preprint 2018

2018 ◽  
Author(s):  
Paolo Moretti
Keyword(s):  
Family History ◽  
Clinical Features ◽  
De Novo ◽  
Severe Disease ◽  
Immunosuppressive Treatment ◽  
Pathogenic Variant ◽  
First Degree Relatives ◽  
Pathogenic Variants ◽  
History Of ◽  
Psychiatric Manifestations

Coffin-Lowry syndrome is an X-linked disease caused by pathogenic variants in RPS6KA3. The disease generally causes severe neurologic and non-neurologic abnormalities in males, and more variable phenotypes in females, including psychiatric manifestations. The majority of cases occur in the absence of known family history of the disease, and women carrying a de novo pathogenic variant may be undiagnosed due to the absence of severe disease manifestations or typically affected first-degree relatives. We describe the clinical features of a woman of normal intellect carrying a novel RPS6KA3 pathogenic variant in whom psychiatric manifestations and encephalopathy responded to immunosuppressive treatment.

scholarly journals Beyond the Brain

Stroke ◽  
2020 ◽  
Vol 51 (10) ◽  
pp. 3007-3017
Author(s):  
Kristiina Rannikmäe ◽  
David E. Henshall ◽  
Sophie Thrippleton ◽  
Qiu Ginj Kong ◽  
Mike Chong ◽  
...  
Keyword(s):  
Transient Ischemic Attack ◽  
Large Scale ◽  
Small Vessel Disease ◽  
Population Based ◽  
Pathogenic Variant ◽  
Pathogenic Variants ◽  
Scale Population ◽  
Underlying Mechanisms ◽  
Ischemic Attack ◽  
Meta Analyses

Background and Purpose: An important minority of cerebral small vessel disease (cSVD) is monogenic. Many monogenic cSVD genes are recognized to be associated with extracerebral phenotypes. We assessed the frequency of these phenotypes in existing literature. Methods: We performed a systematic review following the PRISMA guidelines (Preferred Reporting Items for Systematic Reviews and Meta-Analyses), searching Medline/Embase for publications describing individuals with pathogenic variants in COL4A1/2 , TREX1 , HTRA1 , ADA2 , and CTSA genes (PROSPERO 74804). We included any publication reporting on ≥1 individual with a pathogenic variant and their clinically relevant phenotype. We extracted individuals’ characteristics and information about associated extracerebral phenotypes and stroke/transient ischemic attack. We noted any novel extracerebral phenotypes and looked for shared phenotypes between monogenic cSVDs. Results: After screening 6048 publications, we included 96 COL4A1 (350 individuals), 32 TREX1 (115 individuals), 43 HTRA1 (38 homozygous/61 heterozygous individuals), 16 COL4A2 (37 individuals), 119 ADA2 (209 individuals), and 3 CTSA (14 individuals) publications. The majority of individuals originated from Europe/North America, except for HTRA1 , where most were from Asia. Age varied widely, ADA2 individuals being youngest and heterozygous HTRA1/CTSA individuals oldest. Sex distribution appeared equal. Extracerebral phenotypes were common: 14% to 100% of individuals with a pathogenic variant manifested at least one extracerebral phenotype (14% COL4A2 , 43% HTRA1 heterozygotes, 47% COL4A1 , 57% TREX1 , 91% ADA2 , 94% HTRA1 homozygotes, and 100% CTSA individuals). Indeed, for 4 of 7 genes, an extracerebral phenotype was observed more frequently than stroke/transient ischemic attack. Ocular, renal, hepatic, muscle, and hematologic systems were each involved in more than one monogenic cSVD. Conclusions: Extracerebral phenotypes are common in monogenic cSVD with extracerebral system involvement shared between genes. However, inherent biases in the existing literature mean that further data from large-scale population-based longitudinal studies collecting health outcomes in a systematic unbiased way is warranted. The emerging knowledge will help to select patients for testing, inform clinical management, and provide further insights into the underlying mechanisms of cSVD.

scholarly journals A de novo frameshift pathogenic variant in TBR1 identified in autism without intellectual disability

2020 ◽  
Vol 14 (1) ◽  
Author(s):  
Laurie-Anne Sapey-Triomphe ◽  
Julie Reversat ◽  
Gaëtan Lesca ◽  
Nicolas Chatron ◽  
Marina Bussa ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Magnetic Resonance ◽  
Brain Development ◽  
Language Impairment ◽  
De Novo ◽  
Genetic Alterations ◽  
Autism Spectrum ◽  
Pathogenic Variant ◽  
Pathogenic Variants ◽  
Patient Reported

Abstract Background In order to be able to provide accurate genetic counseling to patients with Autism Spectrum Disorder (ASD), it is crucial to identify correlations between heterogeneous phenotypes and genetic alterations. Among the hundreds of de novo pathogenic variants reported in ASD, single-nucleotide variations and small insertions/deletions were reported in TBR1. This gene encodes a transcription factor that plays a key role in brain development. Pathogenic variants in TBR1 are often associated with severe forms of ASD, including intellectual disability and language impairment. Methods Adults diagnosed with ASD but without intellectual disability (diagnosis of Asperger syndrome, according to the DSM-IV) took part in a genetic consultation encompassing metabolic assessments, a molecular karyotype and the screening of a panel of 268 genes involved in intellectual disability, ASD and epilepsy. In addition, the patient reported here went through a neuropsychological assessment, structural magnetic resonance imaging and magnetic resonance spectroscopy measurements. Results Here, we report the case of a young adult male who presents with a typical form of ASD. Importantly, this patient presents with no intellectual disability or language impairment, despite a de novo heterozygous frameshift pathogenic variant in TBR1, leading to an early premature termination codon (c.26del, p.(Pro9Leufs*12)). Conclusion Based on this case report, we discuss the role of TBR1 in general brain development, language development, intellectual disability and other symptoms of ASD. Providing a detailed clinical description of the individuals with such pathogenic variants should help to understand the genotype-phenotype relationships in ASD.

scholarly journals Spastic paraplegia type 73: expanding phenotype of the first two Brazilian families

2021 ◽  
Author(s):  
Vinícius Lopes Braga ◽  
Wladimir Bocca Vieira de Rezende Pinto ◽  
Bruno de Mattos Lombardi Badia ◽  
José Marcos Vieira de Albuquerque Filho ◽  
Igor Braga Farias ◽  
...  
Keyword(s):  
De Novo ◽  
Current Knowledge ◽  
Spastic Paraparesis ◽  
Pathogenic Variant ◽  
Lower Limbs ◽  
Spastic Paraplegia ◽  
Pathogenic Variants ◽  
Genetic Features ◽  
Age Range ◽  
Late Stages

Context: Hereditary spastic paraplegias (HSPs) represent an expanding group of neurodegenerative diseases characterized mainly by progressive spastic paraparesis of the lower limbs. More than 80 different genetic loci have been associated with HSPs. In 2015, heterozygous pathogenic variants in the CPT1C gene were first associated with SPG73, not yet described in Brazilian patients. Objective: We present clinical, neuroimaging and genetic features of three Brazilian patients with SPG73. Cases reports: We report one male and two female patients, age range 36 to 78 years old. Case 1 presented with a 4-year-history of spasticity, predominantly crural tetraplegia, bladder incontinence, dysphagia and dysphonia. Family history disclosed a sister with epilepsy. Whole-exome sequencing (WES) disclosed a heterozygosis variant c.863G>A (p.Arg288His) in exon 9 of the CPT1C. Cases 2 and 3 are first degree relatives (mother and son). Both presented with long-standing slowly progressive spastic paraplegia. Case 3 presented bladder incontinence, constipation, dysphagia and dysphonia at late stages. Cases 2 and 3 WES disclosed the heterozygosis variant c.196T>G (p.Phe66Val) in exon 4 of the CPT1C. Discussion: Previous literature described six patients from an Italian family with pure HSPs phenotype and the pathogenic variant c.109C>G (p.Arg3. 7Cys) in CPT1C gene. Another group described three patients associated with pure HSPs phenotype and the pathogenic variant (c.226C>T) in the CPT1C gene. All previous reported cases had benign clinical course and bulbar involvement was not described before. One of our cases presented with a de novo variant and rapidly progressive motor and bulbar compromise. Conclusion: our cases expand the current knowledge about SPG73, including a rapidly progressive phenotype with bulbar involvement and cognitive compromise at late stages of disease course.

Changing the landscape of germline testing in patients with pancreatic adenocarcinoma.

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 676-676
Author(s):  
Aly Athens ◽  
Lisa Amacker-North ◽  
Kelly Warsinske ◽  
Kunal C. Kadakia ◽  
Edward S. Kim ◽  
...  
Keyword(s):  
Pathogenic Variant ◽  
Parp Inhibition ◽  
Degree Relative ◽  
Nccn Guidelines ◽  
Variant Of Uncertain Significance ◽  
Cancer Breast ◽  
Pathogenic Variants ◽  
Missed Visits ◽  
History Of ◽  
Germline Testing

676 Background: Results from the POLO trial demonstrated the benefits of PARP inhibition in patients (pts) with germline BRCA-mutated metastatic pancreatic cancer (PC). In 2018, ASCO and NCCN updated their guidelines to recommend that pts with a personal history of PC undergo germline testing. We examined referral patterns and frequency of germline pathogenic variants in pts with PC. Methods: A retrospective review was performed of PC pts seen at the Levine Cancer Institute (LCI) Center for Genetics between January 2010 and September 2019. Descriptive analyses were completed on demographics and appointment outcomes. Results: A total of 201 PC pts were referred; 20 canceled and 14 no-showed their appointment. The remaining 167 were seen and included in this analysis. Most pts (59%) were referred after July 2018. The median age was 65 years (range 32-90) and 19% were < 50 years. The majority of pts were female (61%). Race was most often reported as white (72%) followed by black (20%). Reported family histories were as follows: 28 (17%) claimed at least one first-degree relative with PC; 54 (32%) claimed a first, second, or third-degree relative with PC; 24 (14%) had no known family history of PC; and 95 (57%) claimed a first-degree relative with another cancer (breast [37], prostate [25], colon [18], ovarian [9], uterine [6], and gastric [2]). Germline testing was pursued by 138 (83%) pts: 25 (18%) were found to have a pathogenic variant and 50 (36%) a variant of uncertain significance. Pathogenic variants were most commonly identified in ATM (24%), BRCA2 (20%), PALB2 (12%), and CDKN2A (8%). Variants were also observed in DIS3L2, HOXB13, MITF, MUTYH (heterozygote), NTHL1 (compound heterozygote), RAD50, PRSS1, and SDHA. Among pts that had a pathogenic variant, cascade testing was performed in 11 families (44%) for 29 individuals. Conclusions: Our data suggest that the referral of PC pts to genetics has increased following updated ASCO/NCCN guidelines. However, improved adherence to genetic counseling is needed. ATM and BRCA2 were the most common germline mutations observed. More effort to increase awareness of genetic testing and its potential implications for pts and their families is warranted and might reduce cancellations and missed visits.

scholarly journals Radiation Treatment, ATM, BRCA1/2, and CHEK2*1100delC Pathogenic Variants and Risk of Contralateral Breast Cancer

2020 ◽  
Vol 112 (12) ◽  
pp. 1275-1279 ◽  
Author(s):  
Anne S Reiner ◽  
Mark E Robson ◽  
Lene Mellemkjær ◽  
Marc Tischkowitz ◽  
Esther M John ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Contralateral Breast Cancer ◽  
Contralateral Breast ◽  
Pathogenic Variant ◽  
Chek2 1100Delc ◽  
Variants Of Uncertain Significance ◽  
Missense Variants ◽  
Pathogenic Variants ◽  
Increased Risk ◽  
Uncertain Significance

Abstract Whether radiation therapy (RT) affects contralateral breast cancer (CBC) risk in women with pathogenic germline variants in moderate- to high-penetrance breast cancer–associated genes is unknown. In a population-based case-control study, we examined the association between RT; variants in ATM, BRCA1/2, or CHEK2*1100delC; and CBC risk. We analyzed 708 cases of women with CBC and 1399 controls with unilateral breast cancer, all diagnosed with first invasive breast cancer between 1985 and 2000 and aged younger than 55 years at diagnosis and screened for variants in breast cancer–associated genes. Rate ratios (RR) and 95% confidence intervals (CIs) were estimated using multivariable conditional logistic regression. RT did not modify the association between known pathogenic variants and CBC risk (eg, BRCA1/2 pathogenic variant carriers without RT: RR = 3.52, 95% CI = 1.76 to 7.01; BRCA1/2 pathogenic variant carriers with RT: RR = 4.46, 95% CI = 2.96 to 6.71), suggesting that modifying RT plans for young women with breast cancer is unwarranted. Rare ATM missense variants, not currently identified as pathogenic, were associated with increased risk of RT-associated CBC (carriers of ATM rare missense variants of uncertain significance without RT: RR = 0.38, 95% CI = 0.09 to 1.55; carriers of ATM rare missense variants of uncertain significance with RT: RR = 2.98, 95% CI = 1.31 to 6.80). Further mechanistic studies will aid clinical decision-making related to RT.

scholarly journals C-70 Neuropsychological Profiles of Patients With SCN8A-Related Epilepsy

2019 ◽  
Vol 34 (6) ◽  
pp. 1099-1099
Author(s):  
L Medlin ◽  
L Bello-Espinosa ◽  
N Desire ◽  
W MacAllister
Keyword(s):  
De Novo ◽  
Neuropsychological Functioning ◽  
Pathogenic Variant ◽  
Fine Motor ◽  
Motor Delay ◽  
Compulsive Disorder ◽  
Pathogenic Variants ◽  
Visual Spatial ◽  
Epileptiform Discharges ◽  
Oppositional Defiant

Abstract Objective Two cases of SCN8A-related epilepsy (a sodium-channelopathy) are presented. SCN8A-related epilepsy with encephalopathy (SCN8A-REE), the most common form, is typically characterized by refractory seizures, developmental delays, and intellectual disability (ID) but recently discovered variants have shown broadly normal cognition. Current cases highlight the heterogeneity seen with differing de-novo pathogenic variants. Method Case 1, a 6-year-old right-handed girl, presented with SCN8A-REE and a missense pathogenic variant (c.802A>C), not previously documented. History includes speech and motor delay, with focal motor seizures starting at 4-months. Early EEG showed bilateral centroparietal epileptiform discharges. Case 2, an 8-year-old right-handed girl, presented with SCN8A-related epilepsy with c.5630A>G pathogenic variant with seizure onset at 5-months. Initial EEG showed right occipital spikes. Results Case 1 currently shows motor and language delays and prominent motor tics. Testing documented ID with fairly global neuropsychological deficits (i.e., academics, attention/executive functions, memory, visual-spatial skills, fine motor, language). In contrast, Case 2 shows low average intellect and average academics, but evaluation documented attention deficits, fine motor delays, and behavioral issues in addition to tics; she was diagnosed with Attention-Deficit/Hyperactivity Disorder, Oppositional Defiant Disorder, Obsessive Compulsive Disorder, and Tourette’s. Conclusion These cases expand limited knowledge regarding neuropsychological functioning of children with SCN8A-related epilepsy with unique de-novo pathogenic variants. While SCN8A-REE is clearly associated with ID, other pathogenic variants may show better preserved intellect, despite other neuropsychological and behavioral concerns.

scholarly journals Case Report: Clinical Features of a Chinese Boy With Epileptic Seizures and Intellectual Disabilities Who Carries a Truncated NUS1 Variant

2021 ◽  
Vol 9 ◽  
Author(s):  
Pingli Zhang ◽  
Di Cui ◽  
Peiyuan Liao ◽  
Xiang Yuan ◽  
Nuan Yang ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Clinical Features ◽  
De Novo ◽  
Epileptic Seizures ◽  
Epileptic Encephalopathy ◽  
Chinese Patient ◽  
Pathogenic Variant ◽  
Phenotype Correlation ◽  
Congenital Disorder Of Glycosylation ◽  
Pathogenic Variants

The mental retardation-55 with seizures (MRD55) is a rare genetic disease characterized by developmental delay, intellectual disability, language delay and multiple types of epileptic seizures. It is caused by pathogenic variants of the NUS1 gene, which encodes Nogo-B receptor (NgBR), a necessary subunit for the glycosylation reactions in mammals. To date, 25 disease-causing mutations of NUS1 have been reported, which are responsible for various diseases, including dystonia, Parkinson's disease, developmental and epileptic encephalopathy as well as congenital disorder of glycosylation. In addition, only 9 of these mutations were reported with detailed clinical features. There are no reports about Chinese cases with MRD55. In this study, a novel, de novo pathogenic variant of NUS1 (c.51_54delTCTG, p.L18Tfs*31) was identified in a Chinese patient with intellectual disability and epileptic seizures. This pathogenic variant resulted in truncated NgBR proteins, which might be the cause of the clinical features of the patient. Oxcarbazepine was an effective treatment for improving speech and movement of the patient, who consequently presented with no seizure. With this novel pathogenic variant found in NUS1, we expand the genotype spectrum of MRD55 and provide valuable insights into the potential genotype-phenotype correlation.

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