Dataset Information

Two Novel Compound Heterozygous Mutations in the TRAPPC9 Gene Reveal a Connection of Non-syndromic Intellectual Disability and Autism Spectrum Disorder.

ABSTRACT:

Introduction

Autism spectrum disorder (ASD) is characterized by deficits in communication, social interaction, and repetitive behavior. Up to 70% of ASD cases are linked with intellectual disability (ID). The major genetic causes for ASD and ID are largely unknown, however, a shared genetic etiology between ASD and ID must be assumed. The trafficking protein particle complex subunit 9 (TRAPPC9) is highly expressed in postmitotic neurons of the cerebral cortex, playing a key role in development. Among 43 reported cases with mutations in TRAPPC9, all (100%) showed ID and developmental delay. Among the cases including information about ASD, 26% were affected (19 cases with information, among them 5 with ASD). Nevertheless, in some cases not classified as ASD, descriptions of autistic features like hand-flapping movements were present.

Clinical findings

The affected individual presented with delay of speech development. Physical development was normal. Besides lateral slope of the eye-lid axis no facial abnormalities were evident. The individual was diagnosed with ID and ASD by structured testing. Cerebral MRI revealed associated abnormalities.

Genetical findings

The chromosome set was 46,XY without structural changes. Array-CGH showed a normal molecular karyotype (arr(1-22)x2,(X,Y)x1). PCR for the FMR1 gene showed 41 ± 1 CGG repeats, and therefore no evidence of fragile X syndrome. A panel diagnostic for syndromal ID (CASK, EP300, HIVEP2, KIF1A, TRAPPC9) revealed two structural changes in TRAPPC9 in the compound heterozygosity. The mutations c.1678C > T (p.Arg560Cys) and c.3370C > T (p.Pro1124Ser) are classified as missense mutations and are both not described in the literature.

Conclusion

We report two new missense mutations in the TRAPPC9 gene in one individual with ID and ASD. The TRAPPC9 gene should be part of the diagnostic assessment in ID. ASD must be considered as a feature of TRAPPC9-associated ID. It might have been neglected in the literature and should result in specific testing for ASD in affected individuals.

SUBMITTER: Kramer J

PROVIDER: S-EPMC7947907 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Publications

Two Novel Compound Heterozygous Mutations in the TRAPPC9 Gene Reveal a Connection of Non-syndromic Intellectual Disability and Autism Spectrum Disorder.

Krämer Johannes J Beer Meinrad M Bode Harald H Winter Benedikt B

Frontiers in genetics 20210225

<h4>Introduction</h4>Autism spectrum disorder (ASD) is characterized by deficits in communication, social interaction, and repetitive behavior. Up to 70% of ASD cases are linked with intellectual disability (ID). The major genetic causes for ASD and ID are largely unknown, however, a shared genetic etiology between ASD and ID must be assumed. The trafficking protein particle complex subunit 9 (TRAPPC9) is highly expressed in postmitotic neurons of the cerebral cortex, playing a key role in devel ...[more]

PMID: 33719327

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Project description:Proteins involved in transcriptional regulation harbor a demonstrated enrichment of mutations in neurodevelopmental disorders. The Sin3 (Swi-independent 3)/histone deacetylase (HDAC) complex plays a central role in histone deacetylation and transcriptional repression. Among the two vertebrate paralogs encoding the Sin3 complex, SIN3A variants cause syndromic intellectual disability, but the clinical consequences of SIN3B haploinsufficiency in humans are uncharacterized. Here, we describe a syndrome hallmarked by intellectual disability, developmental delay, and dysmorphic facial features with variably penetrant autism spectrum disorder, congenital malformations, corpus callosum defects, and impaired growth caused by disruptive SIN3B variants. Using chromosomal microarray or exome sequencing, and through international data sharing efforts, we identified nine individuals with heterozygous SIN3B deletion or single-nucleotide variants. Five individuals harbor heterozygous deletions encompassing SIN3B that reside within a ∼230 kb minimal region of overlap on 19p13.11, two individuals have a rare nonsynonymous substitution, and two individuals have a single-nucleotide deletion that results in a frameshift and predicted premature termination codon. To test the relevance of SIN3B impairment to measurable aspects of the human phenotype, we disrupted the orthologous zebrafish locus by genome editing and transient suppression. The mutant and morphant larvae display altered craniofacial patterning, commissural axon defects, and reduced body length supportive of an essential role for Sin3 function in growth and patterning of anterior structures. To investigate further the molecular consequences of SIN3B variants, we quantified genome-wide enhancer and promoter activity states by using H3K27ac ChIP-seq. We show that, similar to SIN3A mutations, SIN3B disruption causes hyperacetylation of a subset of enhancers and promoters in peripheral blood mononuclear cells. Together, these data demonstrate that SIN3B haploinsufficiency leads to a hitherto unknown intellectual disability/autism syndrome, uncover a crucial role of SIN3B in the central nervous system, and define the epigenetic landscape associated with Sin3 complex impairment.

Project description:Proteins involved in transcriptional regulation harbor a demonstrated enrichment of mutations in neurodevelopmental disorders. The Sin3 (Swi-independent 3)/histone deacetylase (HDAC) complex plays a central role in histone deacetylation and transcriptional repression. Among the two vertebrate paralogs encoding the Sin3 complex, SIN3A variants cause syndromic intellectual disability, but the clinical consequences of SIN3B haploinsufficiency in humans are uncharacterized. Here, we describe a syndrome hallmarked by intellectual disability, developmental delay, and dysmorphic facial features with variably penetrant autism spectrum disorder, congenital malformations, corpus callosum defects, and impaired growth caused by disruptive SIN3B variants. Using chromosomal microarray or exome sequencing, and through international data sharing efforts, we identified nine individuals with heterozygous SIN3B deletion or single-nucleotide variants. Five individuals harbor heterozygous deletions encompassing SIN3B that reside within a ~230 kb minimal region of overlap on 19p13.11, two individuals have a rare nonsynonymous substitution, and two individuals have a single-nucleotide deletion that results in a frameshift and predicted premature termination codon. To test the relevance of SIN3B impairment to measurable aspects of the human phenotype, we disrupted the orthologous zebrafish locus by genome editing and transient suppression. The mutant and morphant larvae display altered craniofacial patterning, commissural axon defects, and reduced body length supportive of an essential role for Sin3 function in growth and patterning of anterior structures. To investigate further the molecular consequences of SIN3B variants, we quantified genome-wide enhancer and promoter activity states by using H3K27ac ChIP-seq. We show that, similar to SIN3A mutations, SIN3B disruption causes hyperacetylation of a subset of enhancers and promoters in peripheral blood mononuclear cells. Together, these data demonstrate that SIN3B haploinsufficiency leads to a hitherto unknown intellectual disability/autism syndrome, uncover a crucial role of SIN3B in the central nervous system, and define the epigenetic landscape associated with Sin3 complex impairment.

Project description:Introduction Autism spectrum disorder (ASD) is a highly heterogeneous neurodevelopmental disorder with many contributing risk genes. Multiple intellectual disability (ID) susceptibility genes have been identified in ASDs to date. The trafficking protein particle complex subunit 9 TRAPPC9 (OMIM#611966) in an autosomal recessive intellectual disability (ID) gene associated with not fully penetrant phenotype combining secondary microcephaly, dysmorphic facial features, obesity, autism spectrum disorder (ASD) and attention-deficit hyperactivity disorder (ADHD). Objectives The aim of this study is to consider TRAPPC9 deficiency in autosomal recessive ID with ASD. Methods We present the observation of two siblings, born to Tunisian consanguineous and healthy parents, followed up for syndromic intellectual disability (ID) associated ASD and microcephaly. A clinical exome sequencing was performed to one child using a Trusight One kit of Illumina. We used sanger sequencing to validate the suspected variant for the other child and to specify the parental segregation. Results A homozygous pathogenic variant in the TRAPPC9 (NM_001160372.4) gene, c.1414C > T (p. Arg472Ter) were identified in one child. Sanger sequencing confirmed the homozygosity profile of this variant for the other child while the parents were both heterozygous carriers. Conclusions Repetitive behaviours, especially hand-flapping, were the mean ASD feature in our patients. The current variant is known in the Tunisian population. It is described to lead to the creation of a premature stop codon and a truncating protein causing a TRAPPC9 deficiency. The impairing neuronal NFkB signalling due to TRAPPC9 deficiency has been suggested to be implicated in ASD. Due to the profound ID seen in both patients, we suggest the classification of ASD related to TRAPPC9 deficiency as “secondary” rather than “primary”. Our results support the implication of TRAPPC9 in secondary ASD and shed the light on the possibility of screening p. Arg472Ter in Tunisian patients with this form of ASD as it is a recurrent mutation in the Tunisian population. Disclosure of Interest None Declared

Dataset Information

Two Novel Compound Heterozygous Mutations in the TRAPPC9 Gene Reveal a Connection of Non-syndromic Intellectual Disability and Autism Spectrum Disorder.

Introduction

Clinical findings

Genetical findings

Conclusion

Publications

Two Novel Compound Heterozygous Mutations in the TRAPPC9 Gene Reveal a Connection of Non-syndromic Intellectual Disability and Autism Spectrum Disorder.

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