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1.
Tiana M. Scott Hui Guo Evan E. Eichler Jill A. Rosenfeld Kaifang Pang Zhandong Liu Seema Lalani Weimin Bi Yaping Yang Carlos A. Bacino Haley Streff Andrea M. Lewis Mary K. Koenig Isabelle Thiffault Allison Bellomo David B. Everman Julie R. Jones Roger E. Stevenson Raphael Bernier Christian Gilissen Rolph Pfundt Susan M. Hiatt Gregory M. Cooper Jimmy L. Holder Daryl A. Scott 《Human mutation》2020,41(5):921-925
The bromodomain adjacent to zinc finger 2B gene (BAZ2B) encodes a protein involved in chromatin remodeling. Loss of BAZ2B function has been postulated to cause neurodevelopmental disorders. To determine whether BAZ2B deficiency is likely to contribute to the pathogenesis of these disorders, we performed bioinformatics analyses that demonstrated a high level of functional convergence during fetal cortical development between BAZ2B and genes known to cause autism spectrum disorder (ASD) and neurodevelopmental disorder. We also found an excess of de novo BAZ2B loss‐of‐function variants in exome sequencing data from previously published cohorts of individuals with neurodevelopmental disorders. We subsequently identified seven additional individuals with heterozygous deletions, stop‐gain, or de novo missense variants affecting BAZ2B. All of these individuals have developmental delay (DD), intellectual disability (ID), and/or ASD. Taken together, our findings suggest that haploinsufficiency of BAZ2B causes a neurodevelopmental disorder, whose cardinal features include DD, ID, and ASD. 相似文献
2.
Rose Guo Alyssa L. Rippert Edward B. Cook Cesar Augusto P. Alves Lynne M. Bird Kosuke Izumi 《American journal of medical genetics. Part A》2023,191(10):2602-2609
Eukaryotic translation elongation factor 2 (eEF2), encoded by the gene EEF2, is an essential factor involved in the elongation phase of protein translation. A specific heterozygous missense variant (p.P596H) in EEF2 was originally identified in association with autosomal dominant adult-onset spinocerebellar ataxia-26 (SCA26). More recently, additional heterozygous missense variants in this gene have been described to cause a novel, childhood-onset neurodevelopmental disorder with benign external hydrocephalus. Herein, we report two unrelated individuals with a similar gene-disease correlation to support this latter observation. Patient 1 is a 7-year-old male with a previously reported, de novo missense variant (p.V28M) who has motor and speech delay, autism spectrum disorder, failure to thrive with relative macrocephaly, unilateral microphthalmia with coloboma and eczema. Patient 2 is a 4-year-old female with a novel de novo nonsense variant (p.Q145X) with motor and speech delay, hypotonia, macrocephaly with benign ventricular enlargement, and keratosis pilaris. These additional cases help to further expand the genotypic and phenotypic spectrum of this newly described EEF2-related neurodevelopmental syndrome. 相似文献
3.
Daniela Pasquali Annalaura Torella Anna Grandone Caterina Luongo Manuela Morleo Cristina Peduto Rosa di Fraia Lucia Digitale Selvaggio Francesca Allosso Giacomo Accardo Maria Teresa Zanobio Silvia Maitz Milena Mariani Angelo Selicorni Sandro Banfi Vincenzo Nigro TUDP Study Group 《American journal of medical genetics. Part A》2023,191(3):823-830
Here we describe three patients with neurodevelopmental disorders characterized by mild-to-moderate intellectual disability, mildly dysmorphic features, and hirsutism, all of which carry de novo sequence variants in the WW domain-containing adaptor of the coiled-coil (WAC) gene; two of these—c.167delA, p.(Asn56I1efs*136) and c.1746G>C, p.(Gln582His)—are novel pathogenic variants, and the third—c.1837C>T, p(Arg613*)—has been previously described. Diseases associated with WAC include DeSanto–Shinawi syndrome; to date, de novo heterozygous constitutional pathogenic WAC variants have caused a syndromic form of intellectual disability and mild dysmorphic features in 33 patients, yet potential associations with other clinical manifestations, such as oligomenorrhea and hyperandrogenism, remain unknown, because the phenotypic spectrum of the condition has not yet been delineated. The patient bearing the novel c.167delA WAC gene variant presented a normal psychomotor development, oligomenorrhea, hyperandrogenism, and hirsutism, and hirsutism was also observed in the patient with the c.1746G>C WAC gene variant. Hypertrichosis and hirsutism have been described in nine DeSanto–Shinawi patients, only in 17 of the 33 aforementioned patients thus far reported this aspect, and no hormonal-pattern data are available. In conclusion, we note that the pathogenic c.167delA WAC variant may be associated with a mild phenotype; and in addition to the neurodevelopmental problems nearly all DeSanto–Shinawi patients experience (i.e., intellectual disability and/or developmental delay), we recommend the addition of mild dysmorphic features, hirsutism, and hypertrichosis to this clinical presentation. 相似文献
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Linda M. Reis Nathalie S. Houssin Carlos Zamora Omar Abdul-Rahman Jennifer M. Kalish Elaine H. Zackai Timothy F. Plageman Jr Elena V. Semina 《Clinical genetics》2020,97(3):502-508
Peters anomaly (PA) is a congenital corneal opacity associated with corneo-lenticular attachments. PA can be isolated or part of a syndrome with most cases remaining genetically unsolved. Exome sequencing of a trio with syndromic PA and 145 additional unexplained probands with developmental ocular conditions identified a de novo splicing and three novel missense heterozygous CDH2 variants affecting the extracellular cadherin domains in four individuals with PA. Syndromic anomalies were seen in three individuals and included left-sided cardiac lesions, dysmorphic facial features, and decreasing height percentiles; brain magnetic resonance imaging identified agenesis of the corpus callosum and hypoplasia of the inferior cerebellar vermis. CDH2 encodes for N-cadherin, a transmembrane protein that mediates cell-cell adhesion in multiple tissues. Immunostaining in mouse embryonic eyes confirmed N-cadherin is present in the lens stalk at the time of separation from the future cornea and in the developing lens and corneal endothelium at later stages, supporting a possible role in PA. Previous studies in animal models have noted the importance of Cdh2/cdh2 in the development of the eye, heart, brain, and skeletal structures, also consistent with the patient features presented here. Examination of CDH2 in additional patients with PA is indicated to confirm this association. 相似文献
6.
Gemma L. Carvill Katherine L. Helbig Candace T. Myers Marcello Scala Robert Huether Sara Lewis Tyler N. Kruer Brandon S. Guida Somayeh Bakhtiari Joy Sebe Sha Tang Heather Stickney Sehribani Ulusoy Oktay Ashwin A. Bhandiwad Keri Ramsey Vinodh Narayanan Timothy Feyma Luis O. Rohena Andrea Accogli Mariasavina Severino Georgina Hollingsworth Deepak Gill Christel Depienne Caroline Nava Lynette G. Sadleir Paul A. Caruso Angela E. Lin Floor E. Jansen Bobby Koeleman Eva Brilstra Marjolein H. Willemsen Tjitske Kleefstra Joaquim Sa Marie‐Laure Mathieu Laurine Perrin Gaetan Lesca Pasquale Striano Giorgio Casari Ingrid E. Scheffer David Raible Evelyn Sattlegger Valeria Capra Sergio Padilla‐Lopez Heather C. Mefford Michael C. Kruer 《Human mutation》2020,41(7):1263-1279
Heterozygous de novo variants in the eukaryotic elongation factor EEF1A2 have previously been described in association with intellectual disability and epilepsy but never functionally validated. Here we report 14 new individuals with heterozygous EEF1A2 variants. We functionally validate multiple variants as protein‐damaging using heterologous expression and complementation analysis. Our findings allow us to confirm multiple variants as pathogenic and broaden the phenotypic spectrum to include dystonia/choreoathetosis, and in some cases a degenerative course with cerebral and cerebellar atrophy. Pathogenic variants appear to act via a haploinsufficiency mechanism, disrupting both the protein synthesis and integrated stress response functions of EEF1A2. Our studies provide evidence that EEF1A2 is highly intolerant to variation and that de novo pathogenic variants lead to an epileptic‐dyskinetic encephalopathy with both neurodevelopmental and neurodegenerative features. Developmental features may be driven by impaired synaptic protein synthesis during early brain development while progressive symptoms may be linked to an impaired ability to handle cytotoxic stressors. 相似文献
7.
《Genetics in medicine》2023,25(8):100885
PurposeMissense variants clustering in the BTB domain region of RHOBTB2 cause a developmental and epileptic encephalopathy with early-onset seizures and severe intellectual disability.MethodsBy international collaboration, we assembled individuals with pathogenic RHOBTB2 variants and a variable spectrum of neurodevelopmental disorders. By western blotting, we investigated the consequences of missense variants in vitro.ResultsIn accordance with previous observations, de novo heterozygous missense variants in the BTB domain region led to a severe developmental and epileptic encephalopathy in 16 individuals. Now, we also identified de novo missense variants in the GTPase domain in 6 individuals with apparently more variable neurodevelopmental phenotypes with or without epilepsy. In contrast to variants in the BTB domain region, variants in the GTPase domain do not impair proteasomal degradation of RHOBTB2 in vitro, indicating different functional consequences. Furthermore, we observed biallelic splice-site and truncating variants in 9 families with variable neurodevelopmental phenotypes, indicating that complete loss of RHOBTB2 is pathogenic as well.ConclusionBy identifying genotype-phenotype correlations regarding location and consequences of de novo missense variants in RHOBTB2 and by identifying biallelic truncating variants, we further delineate and expand the molecular and clinical spectrum of RHOBTB2-related phenotypes, including both autosomal dominant and recessive neurodevelopmental disorders. 相似文献
8.
Elliot S. Stolerman Elizabeth Francisco Jennifer L. Stallworth Julie R. Jones Kristin G. Monaghan Jennifer Keller‐Ramey Richard Person Ingrid M. Wentzensen Kirsty McWalter Boris Keren Benedicte Heron Caroline Nava Delphine Heron Katherine Kim Barbara Burton Fatima Al‐Musafri Lauren O'Grady Inderneel Sahai Luis F. Escobar Marije Meuwissen Edwin Reyniers Frank Kooy Yves Lacassie Meral Gunay‐Aygun Krista Sondergaard Schatz Ron Hochstenbach Petra J.G. Zwijnenburg Quinten Waisfisz Marjon van Slegtenhorst Grazia M.S. Mancini Raymond J. Louie 《American journal of medical genetics. Part A》2019,179(7):1276-1286
Lysine‐specific demethylase 6B (KDM6B) demethylates trimethylated lysine‐27 on histone H3. The methylation and demethylation of histone proteins affects gene expression during development. Pathogenic alterations in histone lysine methylation and demethylation genes have been associated with multiple neurodevelopmental disorders. We have identified a number of de novo alterations in the KDM6B gene via whole exome sequencing (WES) in a cohort of 12 unrelated patients with developmental delay, intellectual disability, dysmorphic facial features, and other clinical findings. Our findings will allow for further investigation in to the role of the KDM6B gene in human neurodevelopmental disorders. 相似文献
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Rachel Rabin Alireza Radmanesh Ian A. Glass William B. Dobyns Kimberly A. Aldinger Joseph T. Shieh Shelby Romoser Hannah Bombei Leah Dowsett Pamela Trapane John A. Bernat Janice Baker Nancy J. Mendelsohn Bernt Popp Manuela Siekmeyer Ina Sorge Francis Hugh Sansbury Patrick Watts Nicola C. Foulds Jennifer Burton George Hoganson Jane A. Hurst Lara Menzies Deborah Osio Larissa Kerecuk Jan M. Cobben Khadijé Jizi Sebastien Jacquemont Stacey A. Bélanger Katharina Löhner Hermine E. Veenstra‐Knol Henny H. Lemmink Jennifer Keller‐Ramey Ingrid M. Wentzensen Sumit Punj Kirsty McWalter Jerica Lenberg Katarzyna A. Ellsworth Kelly Radtke Schahram Akbarian John Pappas 《American journal of medical genetics. Part A》2020,182(9):2037-2048
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Ilana Chilton Volkan Okur Giuseppina Vitiello Angelo Selicorni Milena Mariani Alice Goldenberg Thomas Husson Dominique Campion Klaske D. Lichtenbelt Koen van Gassen Michelle Steinraths Jennifer Rice Elizabeth R. Roeder Rebecca O. Littlejohn Myriam Srour Guillaume Sebire Andrea Accogli Delphine Héron Solveig Heide Caroline Nava Christel Depienne Austin Larson Dmitriy Niyazov Meron Azage George Hoganson Jennifer Burton Eric T. Rush Janda L. Jenkins Carol J. Saunders Isabelle Thiffault Joseph T. Alaimo Julie Fleischer Daniel Groepper Karen W. Gripp Wendy K. Chung 《American journal of medical genetics. Part A》2020,182(5):962-973
CDC42BPB encodes MRCKβ (myotonic dystrophy‐related Cdc42‐binding kinase beta), a serine/threonine protein kinase, and a downstream effector of CDC42, which has recently been associated with Takenouchi‐Kosaki syndrome, an autosomal dominant neurodevelopmental disorder. We identified 12 heterozygous predicted deleterious variants in CDC42BPB (9 missense, 2 frameshift, and 1 nonsense) in 14 unrelated individuals (confirmed de novo in 11/14) with neurodevelopmental disorders including developmental delay/intellectual disability, autism, hypotonia, and structural brain abnormalities including cerebellar vermis hypoplasia and agenesis/hypoplasia of the corpus callosum. The frameshift and nonsense variants in CDC42BPB are expected to be gene‐disrupting and lead to haploinsufficiency via nonsense‐mediated decay. All missense variants are located in highly conserved and functionally important protein domains/regions: 3 are found in the protein kinase domain, 2 are in the citron homology domain, and 4 in a 20‐amino acid sequence between 2 coiled‐coil regions, 2 of which are recurrent. Future studies will help to delineate the natural history and to elucidate the underlying biological mechanisms of the missense variants leading to the neurodevelopmental and behavioral phenotypes. 相似文献
11.
Cadherin‐13 gene is associated with hyperactive/impulsive symptoms in attention/deficit hyperactivity disorder
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Angélica Salatino‐Oliveira Julia Pasqualini Genro Guilherme Polanczyk Cristian Zeni Marcelo Schmitz Christian Kieling Luciana Anselmi Ana Maria Baptista Menezes Fernando Cde Barros Evelise Regina Polina Nina R Mota Eugênio Horácio Grevet Claiton Henrique Dotto Bau Luis Augusto Rohde Mara Helena Hutz 《American journal of medical genetics. Part B, Neuropsychiatric genetics》2015,168(3):162-169
Several efforts have been made to find new genetic risk variants which explain the high heritability of ADHD. At the genome level, genes involved in neurodevelopmental pathways were pointed as candidates. CDH13 and CTNNA2 genes are within GWAS top hits in ADHD and there are emerging notions about their contribution to ADHD pathophysiology. The main goal of this study is to test the association between SNPs in CDH13 and CTNNA2 genes and ADHD across the life cycle in subjects with ADHD. This study included 1,136 unrelated ADHD cases and 946 individuals without ADHD. No significant association between CDH13 and CTNNA2 was observed between cases and controls across different samples (P ≥ 0.096 for all comparisons). No allele was significantly more transmitted than expected from parents to ADHD probands. The CDH13 rs11150556 CC genotype was associated with more hyperactive/impulsive symptoms in youths with ADHD (children/adolescents clinical sample: F = 7.666, P = 0.006, FDR P‐value = 0.032; Pelotas Birth Cohort sample: F = 6.711, P = 0.011, FDR P‐value = 0.032). Although there are many open questions regarding the role of neurodevelopmental genes in ADHD symptoms, the present study suggests that CDH13 is associated with hyperactive/impulsive symptoms in youths with ADHD. © 2015 Wiley Periodicals, Inc. 相似文献
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《Genetics in medicine》2023,25(7):100859
PurposeThe study aimed to clinically and molecularly characterize the neurodevelopmental disorder associated with heterozygous de novo variants in CNOT9.MethodsIndividuals were clinically examined. Variants were identified using exome or genome sequencing. These variants were evaluated using in silico predictions, and their functional relevance was further assessed by molecular models and research in the literature. The variants have been classified according to the criteria of the American College of Medical Genetics.ResultsWe report on 7 individuals carrying de novo missense variants in CNOT9, p.(Arg46Gly), p.(Pro131Leu), and p.(Arg227His), and, recurrent in 4 unrelated individuals, p.(Arg292Trp). All affected persons have developmental delay/intellectual disability, with 5 of them showing seizures. Other symptoms include muscular hypotonia, facial dysmorphism, and behavioral abnormalities. Molecular modeling predicted that the variants are damaging and would lead to reduced protein stability or impaired recognition of interaction partners. Functional analyses in previous studies showed a pathogenic effect of p.(Pro131Leu) and p.(Arg227His).ConclusionWe propose CNOT9 as a novel gene for neurodevelopmental disorder and epilepsy. 相似文献
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A novel FBXO28 frameshift mutation in a child with developmental delay,dysmorphic features,and intractable epilepsy: A second gene that may contribute to the 1q41‐q42 deletion phenotype
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Chris Balak Newell Belnap Keri Ramsey Shelagh Joss Koen Devriendt Marcus Naymik Wayne Jepsen Ashley L. Siniard Szabolcs Szelinger Mary E. Parker Ryan Richholt Tyler Izatt Madison LaFleur Panieh Terraf Lorida Llaci Matt De Both Ignazio S. Piras Sampathkumar Rangasamy Isabelle Schrauwen David W. Craig Matt Huentelman Vinodh Narayanan 《American journal of medical genetics. Part A》2018,176(7):1549-1558
Chromosome 1q41‐q42 deletions have recently been associated with a recognizable neurodevelopmental syndrome of early childhood (OMIM 612530). Within this group, a predominant phenotype of developmental delay (DD), intellectual disability (ID), epilepsy, distinct dysmorphology, and brain anomalies on magnetic resonance imaging/computed tomography has emerged. Previous reports of patients with de novo deletions at 1q41‐q42 have led to the identification of an evolving smallest region of overlap which has included several potentially causal genes including DISP1, TP53BP2, and FBXO28. In a recent report, a cohort of patients with de novo mutations in WDR26 was described that shared many of the clinical features originally described in the 1q41‐q42 microdeletion syndrome (MDS). Here, we describe a novel germline FBXO28 frameshift mutation in a 3‐year‐old girl with intractable epilepsy, ID, DD, and other features which overlap those of the 1q41‐q42 MDS. Through a familial whole‐exome sequencing study, we identified a de novo FBXO28 c.972_973delACinsG (p.Arg325GlufsX3) frameshift mutation in the proband. The frameshift and resulting premature nonsense mutation have not been reported in any genomic database. This child does not have a large 1q41‐q42 deletion, nor does she harbor a WDR26 mutation. Our case joins a previously reported patient also in whom FBXO28 was affected but WDR26 was not. These findings support the idea that FBXO28 is a monogenic disease gene and contributes to the complex neurodevelopmental phenotype of the 1q41‐q42 gene deletion syndrome. 相似文献
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Martina Rimoldi Berardo Rinaldi Roberta Villa Jacopo Cerasani Benedetta Beltrami Maria Iascone Rosamaria Silipigni Simona Boito Silvana Gangi Lorenzo Colombo Matteo Porro Claudia Cesaretti Maria Francesca Bedeschi 《American journal of medical genetics. Part A》2023,191(2):605-611
Coffin-Siris Syndrome (CSS) is a rare multi-system dominant condition with a variable clinical presentation mainly characterized by hypoplasia/aplasia of the nail and/or distal phalanx of the fifth digit, coarse facies, hirsutism/hypertrichosis, developmental delay and intellectual disability of variable degree and growth impairment. Congenital anomalies may include cardiac, genitourinary and central nervous system malformations whereas congenital diaphragmatic hernia (CDH) is rarely reported. The genes usually involved in CSS pathogenesis are ARID1B (most frequently), SMARCA4, SMARCB1, ARID1A, SMARCE1, DPF2, and PHF6. Here, we present two cases of CSS presenting with CDH, for whom Whole Exome Sequencing (WES) identified two distinct de novo heterozygous causative variants, one in ARID1B (case 1) and one in SMARCA4 (case 2). Due to the rarity of CDH in CSS, in both cases the occurrence of CDH did not represent a predictive sign of CSS but, on the other hand, prompted genetic testing before (case 1) or independently (case 2) from the clinical hypothesis of CSS. We provide further evidence of the association between CSS and CDH, reviewed previous cases from literature and discuss possible functional links to related conditions. 相似文献
15.
A Gain‐of‐Function Mutation in NALCN in a Child with Intellectual Disability,Ataxia, and Arthrogryposis
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Kyota Aoyagi Elsa Rossignol Fadi F. Hamdan Ben Mulcahy Lin Xie Shinya Nagamatsu Guy A. Rouleau Mei Zhen Jacques L. Michaud 《Human mutation》2015,36(8):753-757
NALCN and its homologues code for the ion channel responsible for half of background Na+‐leak conductance in vertebrate and invertebrate neurons. Recessive mutations in human NALCN cause intellectual disability (ID) with hypotonia. Here, we report a de novo heterozygous mutation in NALCN affecting a conserved residue (p.R1181Q) in a girl with ID, episodic and persistent ataxia, and arthrogryposis. Interestingly, her episodes of ataxia were abolished by the administration of acetazolamide, similar to the response observed in episodic ataxia associated with other ion channels. Introducing the analogous mutation in the Caenorhabditis elegans homologue nca‐1 induced a coiling locomotion phenotype, identical to that obtained with previously characterized C. elegans gain‐of‐function nca alleles, suggesting that p.R1181Q confers the same property to NALCN. This observation thus suggests that dominant mutations in NALCN can cause a neurodevelopmental phenotype that overlaps with, while being mostly distinct from that associated with recessive mutations in the same gene. 相似文献
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Shruti Pande Selinda Mascarenhas Aishwarya Venkatraman Vivekananda Bhat Dhanya Lakshmi Narayanan Shahyan Siddiqui Stephanie Bielas Katta Mohan Girisha Anju Shukla 《American journal of medical genetics. Part A》2023,191(8):2175-2180
Heterozygous disease-causing variants in BCL11B are the basis of a rare neurodevelopmental syndrome with craniofacial and immunological involvement. Isolated craniosynostosis, without systemic or immunological findings, has been reported in one of the 17 individuals reported with this disorder till date. We report three additional individuals harboring de novo heterozygous frameshift variants, all lying in the exon 4 of BCL11B. All three individuals presented with the common findings of this disorder i.e. developmental delay, recurrent infections with immunologic abnormalities and facial dysmorphism. Notably, craniosynostosis of variable degree was seen in all three individuals. We, thus add to the evolving genotypes and phenotypes of BCL11B-related BAFopathy and also review the clinical, genomic spectrum along with the underlying disease mechanisms of this disorder. 相似文献
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《Genetics in medicine》2021,23(8):1465-1473
PurposeWe characterize the clinical and molecular phenotypes of six unrelated individuals with intellectual disability and autism spectrum disorder who carry heterozygous missense variants of the PRKAR1B gene, which encodes the R1β subunit of the cyclic AMP-dependent protein kinase A (PKA).MethodsVariants of PRKAR1B were identified by single- or trio-exome analysis. We contacted the families and physicians of the six individuals to collect phenotypic information, performed in vitro analyses of the identified PRKAR1B-variants, and investigated PRKAR1B expression during embryonic development.ResultsRecent studies of large patient cohorts with neurodevelopmental disorders found significant enrichment of de novo missense variants in PRKAR1B. In our cohort, de novo origin of the PRKAR1B variants could be confirmed in five of six individuals, and four carried the same heterozygous de novo variant c.1003C>T (p.Arg335Trp; NM_001164760). Global developmental delay, autism spectrum disorder, and apraxia/dyspraxia have been reported in all six, and reduced pain sensitivity was found in three individuals carrying the c.1003C>T variant. PRKAR1B expression in the brain was demonstrated during human embryonal development. Additionally, in vitro analyses revealed altered basal PKA activity in cells transfected with variant-harboring PRKAR1B expression constructs.ConclusionOur study provides strong evidence for a PRKAR1B-related neurodevelopmental disorder. 相似文献
19.
The first reported case of an inherited pathogenic CHD2 variant in a clinically affected mother and daughter
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Andrea Klunder Petersen Haley Streff Mari Tokita Bret L. Bostwick 《American journal of medical genetics. Part A》2018,176(7):1667-1669
Pathogenic variants in CHD2 (chromodomain helicase DNA‐binding protein 2) have been reported in neurodevelopmental disorders with a broad spectrum of phenotypic variability, ranging from mild intellectual disability to atonic‐myoclonic epilepsy. However, given the paucity of reported cases the extent of this phenotypic spectrum is currently unknown. Furthermore, all confirmed pathogenic CHD2 variants reported to date have been de novo, preventing the study of intrafamilial phenotypic heterogeneity and creating ambiguity regarding recurrence risk, penetrance, and expressivity. Here, we report the first known case of an inherited pathogenic CHD2 variant in affected mother and daughter. This case demonstrates intrafamilial phenotypic heterogeneity and confirms potential heritability of CHD2‐related neurodevelopmental disorders. 相似文献