Novel missense mutations in PTCHD1 alter its plasma membrane subcellular localization and cause intellectual disability and autism spectrum disorder

IntroductionAutism 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 FindingsThe 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 FindingsThe 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.ConclusionWe 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.

Download Full-text

Biallelic SYNE2 Missense Mutations Leading to Nesprin-2 Giant Hypo-Expression Are Associated with Intellectual Disability and Autism

Genes ◽

10.3390/genes12091294 ◽

2021 ◽

Vol 12 (9) ◽

pp. 1294

Author(s):

Natalie Young ◽

Maria Asif ◽

Matthew Jackson ◽

Daniel Martín Fernández-Mayoralas ◽

Mar Jimenez de la Peña ◽

...

Keyword(s):

Autism Spectrum Disorder ◽

Intellectual Disability ◽

Quantitative Polymerase Chain Reaction ◽

Transcript Level ◽

Autism Spectrum ◽

Spectrum Disorder ◽

Compound Heterozygous ◽

Missense Mutations ◽

Spectrin Repeat ◽

Protein Levels

Autism spectrum disorder (ASD) is a group of neurological and developmental disabilities characterised by clinical and genetic heterogeneity. The current study aimed to expand ASD genotyping by investigating potential associations with SYNE2 mutations. Specifically, the disease-causing variants of SYNE2 in 410 trios manifesting neurodevelopmental disorders using whole-exome sequencing were explored. The consequences of the identified variants were studied at the transcript level using quantitative polymerase chain reaction (qPCR). For validation, immunofluorescence and immunoblotting were performed to analyse mutational effects at the protein level. The compound heterozygous variants of SYNE2 (NM_182914.3:c.2483T>G; p.(Val828Gly) and NM_182914.3:c.2362G>A; p.(Glu788Lys)) were identified in a 4.5-year-old male, clinically diagnosed with autism spectrum disorder, developmental delay and intellectual disability. Both variants reside within the nesprin-2 giant spectrin repeat (SR5) domain and are predicted to be highly damaging using in silico tools. Specifically, a significant reduction of nesprin-2 giant protein levels is revealed in patient cells. SYNE2 transcription and the nuclear envelope localisation of the mutant proteins was however unaffected as compared to parental control cells. Collectively, these data provide novel insights into the cardinal role of the nesprin-2 giant in neurodevelopment and suggest that the biallelic hypomorphic SYNE2 mutations may be a new cause of intellectual disability and ASD.

Download Full-text