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Open accessJournal ArticleDOI: 10.1016/J.AJHG.2021.01.015

SPEN haploinsufficiency causes a neurodevelopmental disorder overlapping proximal 1p36 deletion syndrome with an episignature of X chromosomes in females

04 Mar 2021-American Journal of Human Genetics (Cell Press)-Vol. 108, Iss: 3, pp 502-516
Abstract: 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.

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Topics: 1p36 deletion syndrome (57%), Haploinsufficiency (54%), Neurodevelopmental disorder (54%) ... read more
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13 results found


Journal ArticleDOI: 10.1016/J.AJHG.2021.06.015
Abstract: DNA methylation (DNAm) signatures are unique patterns of DNAm alterations defined for rare disorders caused by pathogenic variants in epigenetic regulatory genes. The potential of DNAm signatures (also known as "episignatures") is just beginning to emerge as there are >300 known epigenetic regulatory genes, ∼100 of which are linked to neurodevelopmental disorders. To date, approximately 50 signatures have been identified, which have proven unexpectedly successful as predictive tools for classifying variants of uncertain significance as pathogenic or benign. The molecular basis of these signatures is poorly understood. Furthermore, their relationships to primary disease pathophysiology have yet to be adequately investigated, despite clear demonstrations of potential connections. There are currently no published guidelines for signature development. As signatures are highly dependent on the samples and methods used to derive them, we propose a framework for consideration in signature development including sample size, statistical parameters, cell type of origin, and the value of detailed clinical and molecular information. We illustrate the relationship between signature output/efficacy and sample size by generating and testing 837 DNAm signatures of Kleefstra syndrome using downsampling analysis. Our findings highlight that no single DNAm signature encompasses all DNAm alterations present in a rare disorder, and that a substandard study design can generate a DNAm signature that misclassifies variants. Finally, we discuss the importance of further investigating DNAm signatures to inform disease pathophysiology and broaden their scope as a functional assay.

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Topics: dNaM (70%)

4 Citations


Open accessJournal ArticleDOI: 10.1007/S00439-021-02283-2
Ilaria Parenti1, Daphné Lehalle2, Caroline Nava2, Erin Torti3  +41 moreInstitutions (19)
04 May 2021-Human Genetics
Abstract: Located in the critical 1p36 microdeletion region, the chromodomain helicase DNA-binding protein 5 (CHD5) gene encodes a subunit of the nucleosome remodeling and deacetylation (NuRD) complex required for neuronal development. Pathogenic variants in six of nine chromodomain (CHD) genes cause autosomal dominant neurodevelopmental disorders, while CHD5-related disorders are still unknown. Thanks to GeneMatcher and international collaborations, we assembled a cohort of 16 unrelated individuals harboring heterozygous CHD5 variants, all identified by exome sequencing. Twelve patients had de novo CHD5 variants, including ten missense and two splice site variants. Three familial cases had nonsense or missense variants segregating with speech delay, learning disabilities, and/or craniosynostosis. One patient carried a frameshift variant of unknown inheritance due to unavailability of the father. The most common clinical features included language deficits (81%), behavioral symptoms (69%), intellectual disability (64%), epilepsy (62%), and motor delay (56%). Epilepsy types were variable, with West syndrome observed in three patients, generalized tonic-clonic seizures in two, and other subtypes observed in one individual each. Our findings suggest that, in line with other CHD-related disorders, heterozygous CHD5 variants are associated with a variable neurodevelopmental syndrome that includes intellectual disability with speech delay, epilepsy, and behavioral problems as main features.

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Topics: Intellectual disability (55%), Speech delay (54%), Neurodevelopmental disorder (53%) ... read more

2 Citations


Open accessJournal ArticleDOI: 10.3390/GENES12070950
22 Jun 2021-Genes
Abstract: One of the recently described syndromes emerging from the massive study of cohorts of undiagnosed patients with autism spectrum disorders (ASD) and syndromic intellectual disability (ID) is White–Sutton syndrome (WHSUS) (MIM #616364), caused by variants in the POGZ gene (MIM *614787), located on the long arm of chromosome 1 (1q21.3). So far, more than 50 individuals have been reported worldwide, although phenotypic features and natural history have not been exhaustively characterized yet. The phenotypic spectrum of the WHSUS is broad and includes moderate to severe ID, microcephaly, variable cerebral malformations, short stature, brachydactyly, visual abnormalities, sensorineural hearing loss, hypotonia, sleep difficulties, autistic features, self-injurious behaviour, feeding difficulties, gastroesophageal reflux, and other less frequent features. Here, we report the case of a girl with microcephaly, brain malformations, developmental delay (DD), peripheral polyneuropathy, and adducted thumb—a remarkable clinical feature in the first years of life—and heterozygous for a previously unreported, de novo splicing variant in POGZ. This report contributes to strengthen and expand the knowledge of the clinical spectrum of WHSUS, pointing out the importance of less frequent clinical signs as diagnostic handles in suspecting this condition.

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Topics: Microcephaly (54%), Hypotonia (53%), Brachydactyly (52%)

1 Citations


Open accessJournal ArticleDOI: 10.3390/GENES12081208
05 Aug 2021-Genes
Abstract: Lissencephaly describes a group of conditions characterized by the absence of normal cerebral convolutions and abnormalities of cortical development. To date, at least 20 genes have been identified as involved in the pathogenesis of this condition. Variants in CEP85L, encoding a protein involved in the regulation of neuronal migration, have been recently described as causative of lissencephaly with a posterior-prevalent involvement of the cerebral cortex and an autosomal dominant pattern of inheritance. Here, we describe a 3-year-old boy with slightly delayed psychomotor development and mild dysmorphic features, including bitemporal narrowing, protruding ears with up-lifted lobes and posterior plagiocephaly. Brain MRI at birth identified type 1 lissencephaly, prevalently in the temporo-occipito-parietal regions of both hemispheres with "double-cortex" (Dobyns' 1-2 degree) periventricular band alterations. Whole-exome sequencing revealed a previously unreported de novo pathogenic variant in the CEP85L gene (NM_001042475.3:c.232+1del). Only 20 patients have been reported as carriers of pathogenic CEP85L variants to date. They show lissencephaly with prevalent posterior involvement, variable cognitive deficits and epilepsy. The present case report indicates the clinical variability associated with CEP85L variants that are not invariantly associated with severe phenotypes and poor outcome, and underscores the importance of including this gene in diagnostic panels for lissencephaly.

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Topics: Lissencephaly (68%)

Open accessJournal ArticleDOI: 10.3390/GENES12071009
30 Jun 2021-Genes
Abstract: Objective, the application of genomic sequencing in clinical practice has allowed us to appreciate the contribution of co-occurring pathogenic variants to complex and unclassified clinical phenotypes. Besides the clinical relevance, these findings have provided evidence of previously unrecognized functional links between genes in the context of developmental processes and physiology. Patients and Methods, a 5-year-old patient showing an unclassified phenotype characterized by developmental delay, speech delay, peculiar behavioral features, facial dysmorphism and severe cardiopathy was analyzed by trio-based whole exome sequencing (WES) analysis to identify the genomic events underlying the condition. Results, two co-occurring heterozygous truncating variants in CNOT3 and SMAD6 were identified. Heterozygous loss-of-function variants in CNOT3, encoding a subunit of the CCR4-NOT protein complex, have recently been reported to cause a syndromic condition known as intellectual developmental disorder with speech delay, autism and dysmorphic facies (IDDSADF). Enrichment of rare/private variants in the SMAD6 gene, encoding a protein negatively controlling transforming growth factor β/bone morphogenetic protein (TGFB/BMP) signaling, has been described in association with a wide spectrum of congenital heart defects. We dissected the contribution of individual variants to the complex clinical manifestations and profiled a previously unappreciated set of facial features and signs characterizing IDDSADF. Conclusions, two concomitant truncating variants in CNOT3 and SMAD6 are the cause of the combination of features documented in the patient resulting in the unique multisystem neurodevelopmental condition. These findings provide evidence for a functional link between the CCR4-NOT complex and TGFB/BMP signaling in processes controlling cardiac development. Finally, the present revision provides evidence that IDDSADF is characterized by a distinctive facial gestalt.

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Topics: Exome sequencing (54%), Speech delay (51%)

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76 results found


Open accessJournal ArticleDOI: 10.1038/NATURE13908
Ivan Iossifov1, Brian J. O'Roak2, Stephen Sanders3, Stephen Sanders4  +49 moreInstitutions (8)
13 Nov 2014-Nature
Abstract: Whole exome sequencing has proven to be a powerful tool for understanding the genetic architecture of human disease. Here we apply it to more than 2,500 simplex families, each having a child with an autistic spectrum disorder. By comparing affected to unaffected siblings, we show that 13% of de novo missense mutations and 43% of de novo likely gene-disrupting (LGD) mutations contribute to 12% and 9% of diagnoses, respectively. Including copy number variants, coding de novo mutations contribute to about 30% of all simplex and 45% of female diagnoses. Almost all LGD mutations occur opposite wild-type alleles. LGD targets in affected females significantly overlap the targets in males of lower intelligence quotient (IQ), but neither overlaps significantly with targets in males of higher IQ. We estimate that LGD mutation in about 400 genes can contribute to the joint class of affected females and males of lower IQ, with an overlapping and similar number of genes vulnerable to contributory missense mutation. LGD targets in the joint class overlap with published targets for intellectual disability and schizophrenia, and are enriched for chromatin modifiers, FMRP-associated genes and embryonically expressed genes. Most of the significance for the latter comes from affected females.

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Topics: Exome (52%), Exome sequencing (50%)

1,721 Citations


Open accessJournal ArticleDOI: 10.1038/NATURE10523
Hyo Jung Kang1, Yuka Imamura Kawasawa1, Feng Cheng1, Ying Zhu1  +26 moreInstitutions (7)
27 Oct 2011-Nature
Abstract: Brain development and function depend on the precise regulation of gene expression. However, our understanding of the complexity and dynamics of the transcriptome of the human brain is incomplete. Here we report the generation and analysis of exon-level transcriptome and associated genotyping data, representing males and females of different ethnicities, from multiple brain regions and neocortical areas of developing and adult post-mortem human brains. We found that 86 per cent of the genes analysed were expressed, and that 90 per cent of these were differentially regulated at the whole-transcript or exon level across brain regions and/or time. The majority of these spatio-temporal differences were detected before birth, with subsequent increases in the similarity among regional transcriptomes. The transcriptome is organized into distinct co-expression networks, and shows sex-biased gene expression and exon usage. We also profiled trajectories of genes associated with neurobiological categories and diseases, and identified associations between single nucleotide polymorphisms and gene expression. This study provides a comprehensive data set on the human brain transcriptome and insights into the transcriptional foundations of human neurodevelopment.

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1,502 Citations


Open accessJournal ArticleDOI: 10.1016/J.AJHG.2009.03.010
Abstract: Many patients suffering from developmental disorders harbor submicroscopic deletions or duplications that, by affecting the copy number of dosage-sensitive genes or disrupting normal gene expression, lead to disease. However, many aberrations are novel or extremely rare, making clinical interpretation problematic and genotype-phenotype correlations uncertain. Identification of patients sharing a genomic rearrangement and having phenotypic features in common leads to greater certainty in the pathogenic nature of the rearrangement and enables new syndromes to be defined. To facilitate the analysis of these rare events, we have developed an interactive web-based database called DECIPHER (Database of Chromosomal Imbalance and Phenotype in Humans Using Ensembl Resources) which incorporates a suite of tools designed to aid the interpretation of submicroscopic chromosomal imbalance, inversions, and translocations. DECIPHER catalogs common copy-number changes in normal populations and thus, by exclusion, enables changes that are novel and potentially pathogenic to be identified. DECIPHER enhances genetic counseling by retrieving relevant information from a variety of bioinformatics resources. Known and predicted genes within an aberration are listed in the DECIPHER patient report, and genes of recognized clinical importance are highlighted and prioritized. DECIPHER enables clinical scientists worldwide to maintain records of phenotype and chromosome rearrangement for their patients and, with informed consent, share this information with the wider clinical research community through display in the genome browser Ensembl. By sharing cases worldwide, clusters of rare cases having phenotype and structural rearrangement in common can be identified, leading to the delineation of new syndromes and furthering understanding of gene function.

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Topics: DECIPHER (61%), Ensembl (54%), Chromosomal rearrangement (54%) ... read more

1,245 Citations


Journal ArticleDOI: 10.1056/NEJMOA1206524
Abstract: Background The causes of intellectual disability remain largely unknown because of extensive clinical and genetic heterogeneity. Methods We evaluated patients with intellectual disability to exclude known causes of the disorder. We then sequenced the coding regions of more than 21,000 genes obtained from 100 patients with an IQ below 50 and their unaffected parents. A data-analysis procedure was developed to identify and classify de novo, autosomal recessive, and X-linked mutations. In addition, we used high-throughput resequencing to confirm new candidate genes in 765 persons with intellectual disability (a confirmation series). All mutations were evaluated by molecular geneticists and clinicians in the context of the patients' clinical presentation. Results We identified 79 de novo mutations in 53 of 100 patients. A total of 10 de novo mutations and 3 X-linked (maternally inherited) mutations that had been previously predicted to compromise the function of known intellectual-disability genes were found in 13 patients. Potentially causative de novo mutations in novel candidate genes were detected in 22 patients. Additional de novo mutations in 3 of these candidate genes were identified in patients with similar phenotypes in the confirmation series, providing support for mutations in these genes as the cause of intellectual disability. We detected no causative autosomal recessive inherited mutations in the discovery series. Thus, the total diagnostic yield was 16%, mostly involving de novo mutations. Conclusions De novo mutations represent an important cause of intellectual disability; exome sequencing was used as an effective diagnostic strategy for their detection. (Funded by the European Union and others.).

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Topics: Exome sequencing (55%), Intellectual disability (55%), Candidate gene (52%) ... read more

1,133 Citations


Open accessJournal ArticleDOI: 10.1073/PNAS.97.23.12729
Abstract: Estrogen regulates the amount of white adipose tissue (WAT) in females, but its role in males and whether WAT effects involve estrogen receptor-α (ERα) or ERβ were unclear. We analyzed the role of ERα in WAT and brown adipose tissue by comparing these tissues in wild-type (WT) and ERα-knockout (αERKO) male and female mice. Brown adipose tissue weight was similar in αERKO and WT males at all ages. Progressive increases in WAT were seen in αERKO males with advancing age. Epididymal, perirenal, and inguinal WAT weighed 139–185% more in αERKO than in WT males by 270–360 days of age. Epididymal and perirenal adipocyte size was increased 20% in αERKO males. Adipocyte number was 82–168% greater in fat pads of αERKO vs. WT males. Compared with WT, 90-day-old αERKO females had increases in fat pad weights (54–103%), adipocyte size, and number. Both αERKO males and females had insulin resistance and impaired glucose tolerance, similar to humans lacking ERα or aromatase. Energy intake was equal in WT and αERKO males, indicating that obesity was not induced by hyperphagia. In contrast, energy expenditure was reduced by 11% in αERKO compared with WT males, indicating that altered energy expenditure may be important for the observed obesity. In summary, ERα absence causes adipocyte hyperplasia and hypertrophy, insulin resistance, and glucose intolerance in both sexes. These results are evidence that estrogen/ERα signaling is critical in female and male WAT; obesity in αERKO males involves a mechanism of reduced energy expenditure rather than increased energy intake.

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Topics: Adipose tissue (54%), White adipose tissue (54%), Adipocyte (52%) ... read more

1,071 Citations