Pathogenic variants in ATP-dependent chromatin remodeling proteins are a recurrent cause of neurodevelopmental disorders (NDDs). The NURF complex consists of BPTF and either the SMARCA5 or SMARCA1 ISWI-chromatin remodeling enzyme. Pathogenic variants in BPTF and SMARCA5 have been previously implicated in NDDs. Here, we describe 35 individuals from 26 families with de novo or maternally inherited variants in the X-linked SMARCA1 gene. This SMARCA1-related NDD is associated with a spectrum of involvement, including mild to severe ID/DD, delayed or regressive speech development, ASD features, facial dysmorphisms, and other variable features. Individuals carrying SMARCA1 truncating variants exhibit a mildly unique genome-wide DNA methylation profile and a high penetrance of macrocephaly. Genetic dissection of the NURF complex using Smarca1, Smarca5, and Bptf single and double mouse knockouts reveals the importance of NURF composition and dosage for proper forebrain development. We propose that genetic alterations affecting different NURF components, including SMARCA1, result in a NDD with a broad clinical spectrum.

Pathogenic variants in ATP-dependent chromatin remodeling proteins are a recurrent cause of neurodevelopmental disorders (NDDs). The NURF complex consists of BPTF and either the SNF2H (SMARCA5) or SNF2L (SMARCA1) ISWI-chromatin remodeling enzyme. Pathogenic variants in BPTF and SMARCA5 were previously implicated in NDDs. Here, we describe 40 individuals from 30 families with de novo or maternally inherited pathogenic variants in SMARCA1. This novel NDD was associated with mild to severe ID/DD, delayed or regressive speech development, and some recurrent facial dysmorphisms. Individuals carrying SMARCA1 loss-of-function variants exhibited a mild genome-wide DNA methylation profile and a high penetrance of macrocephaly. Genetic dissection of the NURF complex using Smarca1, Smarca5, and Bptfsingle and double mouse knockouts revealed the importance of NURF composition and dosage for proper forebrain development. Finally, we propose that genetic alterations affecting different NURF components result in a NDD with a broad clinical spectrum.

NCKAP1/NAP1 regulates neuronal cytoskeletal dynamics and is essential for neuronal differentiation in the developing brain. Deleterious variants in NCKAP1 have been identified in individuals with autism spectrum disorder (ASD) and intellectual disability; however, its clinical significance remains unclear. To determine its significance, we assemble genotype and phenotype data for 21 affected individuals from 20 unrelated families with predicted deleterious variants in NCKAP1. This includes 16 individuals with de novo (n = 8), transmitted (n = 6), or inheritance unknown (n = 2) truncating variants, two individuals with structural variants, and three with potentially disruptive de novo missense variants. We report a de novo and ultra-rare deleterious variant burden of NCKAP1 in individuals with neurodevelopmental disorders which needs further replication. ASD or autistic features, language and motor delay, and variable expression of intellectual or learning disability are common clinical features. Among inherited cases, there is evidence of deleterious variants segregating with neuropsychiatric disorders. Based on available human brain transcriptomic data, we show that NCKAP1 is broadly and highly expressed in both prenatal and postnatal periods and demostrate enriched expression in excitatory neurons and radial glias but depleted expression in inhibitory neurons. Mouse in utero electroporation experiments reveal that Nckap1 loss of function promotes neuronal migration during early cortical development. Combined, these data support a role for disruptive NCKAP1 variants in neurodevelopmental delay/autism, possibly by interfering with neuronal migration early in cortical development.

PCGF2 encodes the polycomb group ring finger 2 protein, a transcriptional repressor involved in cell proliferation, differentiation, and embryogenesis. PCGF2 is a component of the polycomb repressive complex 1 (PRC1), a multiprotein complex which controls gene silencing through histone modification and chromatin remodelling. We report the phenotypic characterization of 13 patients (11 unrelated individuals and a pair of monozygotic twins) with missense mutations in PCGF2. All the mutations affected the same highly conserved proline in PCGF2 and were de novo, excepting maternal mosaicism in one. The patients demonstrated a recognizable facial gestalt, intellectual disability, feeding problems, impaired growth, and a range of brain, cardiovascular, and skeletal abnormalities. Computer structural modeling suggests the substitutions alter an N-terminal loop of PCGF2 critical for histone biding. Mutant PCGF2 may have dominant-negative effects, sequestering PRC1 components into complexes that lack the ability to interact efficiently with histones. These findings demonstrate the important role of PCGF2 in human development and confirm that heterozygous substitutions of the Pro65 residue of PCGF2 cause a recognizable syndrome characterized by distinctive craniofacial, neurological, cardiovascular, and skeletal features.

American Journal of Medical Genetics Part AVolume 167, Issue 6 p. 1421-1422 Research Letter Gnathodiaphyseal dysplasia presenting as polyostotic fibrous dysplasia Jaime Vengoechea, Jaime Vengoechea Division of Genetics, University of Arkansas for Medical Sciences College of Medicine, Little Rock, ArkansasSearch for more papers by this authorLori Carpenter, Corresponding Author Lori Carpenter Division of Genetics, University of Arkansas for Medical Sciences College of Medicine, Little Rock, Arkansas Correspondence to: Jaime Vengoechea, Division of Genetics, University of Arkansas for Medical Sciences College of Medicine, 4301 W Markham St. Slot 514, Little Rock, AR 72205, US. E-mail: jaimevengoechea@gmail.comSearch for more papers by this author Jaime Vengoechea, Jaime Vengoechea Division of Genetics, University of Arkansas for Medical Sciences College of Medicine, Little Rock, ArkansasSearch for more papers by this authorLori Carpenter, Corresponding Author Lori Carpenter Division of Genetics, University of Arkansas for Medical Sciences College of Medicine, Little Rock, Arkansas Correspondence to: Jaime Vengoechea, Division of Genetics, University of Arkansas for Medical Sciences College of Medicine, 4301 W Markham St. Slot 514, Little Rock, AR 72205, US. E-mail: jaimevengoechea@gmail.comSearch for more papers by this author First published: 10 April 2015 https://doi.org/10.1002/ajmg.a.36986Citations: 11Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article.Citing Literature Volume167, Issue6June 2015Pages 1421-1422 RelatedInformation

American Journal of Medical Genetics Part AVolume 164, Issue 7 p. 1857-1859 Research Letter Papillary thyroid cancer in a patient with interstitial 6q25 deletion including ARID1B Jaime Vengoechea, Corresponding Author Jaime Vengoechea Divison of Genetics, University of Arkansas for Medical Sciences College of Medicine, Little Rock, Arkansas Correspondence to: Jaime Vengoechea, M.D., 4301W Markham St, Slot 514, Little Rock, AR 72202. E-mail: [email protected]Search for more papers by this authorLori Carpenter, Lori Carpenter Divison of Genetics, University of Arkansas for Medical Sciences College of Medicine, Little Rock, ArkansasSearch for more papers by this authorYuri A. Zárate, Yuri A. Zárate Divison of Genetics, University of Arkansas for Medical Sciences College of Medicine, Little Rock, ArkansasSearch for more papers by this author Jaime Vengoechea, Corresponding Author Jaime Vengoechea Divison of Genetics, University of Arkansas for Medical Sciences College of Medicine, Little Rock, Arkansas Correspondence to: Jaime Vengoechea, M.D., 4301W Markham St, Slot 514, Little Rock, AR 72202. E-mail: [email protected]Search for more papers by this authorLori Carpenter, Lori Carpenter Divison of Genetics, University of Arkansas for Medical Sciences College of Medicine, Little Rock, ArkansasSearch for more papers by this authorYuri A. Zárate, Yuri A. Zárate Divison of Genetics, University of Arkansas for Medical Sciences College of Medicine, Little Rock, ArkansasSearch for more papers by this author First published: 03 April 2014 https://doi.org/10.1002/ajmg.a.36515Citations: 15Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. 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Amyotrophic lateral sclerosis (ALS) is a degenerative motor neuron disease leading to progressive paralysis that is generally fatal. Only 10% of cases are familial, a subset of which overlaps with frontotemporal dementia (FTD). Up to half of ALS patients have cognitive impairment, with 15% meeting the criteria for FTD. Clinical sequencing of UBQLN2 in a family with X-linked FTD/ALS with suspected incomplete penetrance, manifesting in both genders, revealed a P506S mutation in. Affected individuals were diagnosed with various conditions including hereditary spastic paraplegia (HSP), bulbar palsy and multiple sclerosis. The mutation in UBQLN2 was first identified in a 35-year-old female who presented with one year of progressive dysarthria, dyspnea, dysphagia, and cognitive decline. EMG suggested early motor neuron disease with prominent bulbar involvement. Her cognition declined rapidly and she developed extremity weakness. Her brother, initially diagnosed with HSP, and her second cousin, with primary lateral sclerosis, also have a P506S mutation in UBQLN2. In conclusion, the P506S mutation in UBQLN2 can affect both males and females and displays great phenotypic variability within the same family. Females can potentially have a more severe and rapidly progressive presentation than their male relatives. Additionally, the P506S mutation can also cause an FTD phenotype.