Identification of two novel homozygous nonsense mutations in TRAPPC9 in two unrelated consanguineous families with intellectual Disability from Iran

Yousefipour, Farideh; Mozhdehipanah, Hossein; Mahjoubi, Frouzandeh

doi:10.1002/mgg3.1610

Cited by 10 publications

(7 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To our knowledge, this is the first reported patient of Hispanic ancestry. Our case further delineates the TRAPPC9 ‐related phenotype as it adds to the number of reported cases with cleft lip/palate (four cases with our patient) and autism spectrum disorder (five cases including our case), features that may be part of the phenotypic spectrum of this condition (Hnoonual et al, 2019; Yousefipour et al, 2021). This report also underlines the strengths of combining orthologous methods to establish a diagnosis and emphasizes implications of downstream analysis from UPD/ROH given the increased risk for autosomal recessive conditions.…”

Section: Discussionsupporting

confidence: 73%

“…613192), also characterized by microcephaly, hypo/hypertelorism, obesity, growth delay, behavioral differences, and central nervous system abnormalities. To date, ~53 cases have been reported in the medical literature (Abbasi et al, 2017; Abou Jamra et al, 2011; Alvarez‐Mora et al, 2021; Giorgio et al, 2016; Hnoonual et al, 2019; Krämer et al, 2021; Marangi et al, 2013; Mir et al, 2009; Mochida et al, 2009; Radenkovic et al, 2022; Wilton et al, 2020; Yousefipour et al, 2021; Zhouxian & Xiangdong, 2019).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

TRAPPC9‐related neurodevelopmental disorder: Report of a homozygous deletion in TRAPPC9 due to paternal uniparental isodisomy

Penón-Portmann

Hodoğlugil

et al. 2022

American J of Med Genetics Pt A

View full text Add to dashboard Cite

TRAPPC9 loss‐of‐function biallelic variants are associated with an autosomal recessive intellectual disability syndrome (Online Mendelian Inheritance of Man no. 613192), also characterized by microcephaly, hypertelorism, obesity, growth delay, and behavioral differences. Here, we describe an 8‐year‐old Hispanic female with neurodevelopmental disorder, partial epilepsy, microcephaly, bilateral cleft lip and alveolus, growth delay, and dysmorphic features. She had abnormal myelination, mega cisterna magna, and colpocephaly on brain magnetic resonance imaging (MRI). Microarray showed a single ~146 Mb region of homozygosity (ROH) encompassing all of Chromosome 8, consistent with uniparental isodisomy (UPD). Exome sequencing performed in‐house did not identify single nucleotide variants to explain her phenotype. Algorithms developed in‐house and further evaluation of BAM files revealed a homozygous deletion overlapping Exon 2 in TRAPPC9 within the ROH. Subsequent del/dup analyses with exon‐level oligo array confirmed a likely pathogenic deletion in TRAPPC9 (NM_031466.5): arr[GRCh37] 8q24.3(141460661_141461780)x0. Our case highlights the implications of downstream analyses from UPD/ROH given the increased risk for AR conditions, the strengths of combining orthologous molecular methods to establish a diagnosis and further delineates the TRAPPC9‐related phenotype in an individual of Hispanic ancestry.

show abstract

Section: Discussionsupporting

confidence: 73%

Section: Introductionmentioning

confidence: 99%

TRAPPC9‐related neurodevelopmental disorder: Report of a homozygous deletion in TRAPPC9 due to paternal uniparental isodisomy

Penón-Portmann

Hodoğlugil

et al. 2022

American J of Med Genetics Pt A

View full text Add to dashboard Cite

show abstract

“…To date, 27 different point mutations have been reported in the patients with TRAPPC9-related ID (Fig. 3b) [Mir et al, 2009;Mochida et al, 2009;Philippe et al, 2009;Koifman et al, 2010;Abou Jamra et al, 2011;Kakar et al, 2012;Marangi et al, 2013;Giorgio et al, 2016;Abbasi et al, 2017;Mortreux et al, 2018;Bai and Kong, 2019;Boonsawat et al, 2019;Hnoonual et al, 2019;Wilton et al, 2020;Alvarez-Mora et al, 2021;Ben Ayed et al, 2021;Yousefipour et al, 2021;Aslanger et al, 2022;Bolat et al, 2022;Radenkovic et al, 2022]. These mutations are scattered throughout all exons of TRAPPC9 indicating there is no hot spot mutation region in this gene and every exon has a critical role in proper functioning of TRAPPC9.…”

Section: Discussionmentioning

confidence: 99%

“…Trafficking protein particle complex subunit 9 gene (TRAPPC9; OMIM #611966) plays a critical role in the neuronal NF-kB signaling pathways and is one of the numerous genes involved in the AR-ID. Patients with pathogenic biallelic variants of TRAPPC9 have been manifested as ID, developmental delay (DD), microcephaly, autistic features, and brain abnormalities on MRI investigations [Yousefipour et al, 2021].…”

Section: Introductionmentioning

confidence: 99%

TRAPPC9-Related Intellectual Disability: Report of Two New Cases and Review of the Literature

Uctepe,

Yesilyurt,

Esen

et al. 2023

Mol Syndromol

View full text Add to dashboard Cite

Introduction: Hereditary forms of intellectual disability (ID), an estimated prevalence ranging between 1% and 3% in the general population, are among the most important problems in health care. Especially, autosomal-recessive ID has a very heterogeneous molecular basis and a lack of specific phenotypic features. Methods: Here, we report on two unrelated patients with autosomal-recessive ID, microcephaly, and autistic features and review the patients with TRAPPC9-related ID. Whole-exome sequencing and array CGH were performed for molecular diagnosis of the patients. Results: The first case has a microdeletion on chromosome 8q24.23-q24.3 region which is 1.7 Mb in length and includes the last 5 exons of TRAPPC9, and c.3435delG [p.Thr1146Profs*8] deletion. The second case has a homozygous missense c.623A>C (p.His208Pro) variant in TRAPPC9 which is detected by means of whole-exome sequencing study of the proband. We also reviewed the clinical findings and mutation spectrum of all patients with TRAPPC9-related ID reported so far. Conclusions: Our study showed that the most consistent clinical findings for TRAPPC9-related ID are ID, microcephaly, and some structural brain MRI abnormalities. The mutations in the TRAPPC9 are scattered throughout all exons of TRAPPC9 indicating there is no hot spot mutation region in this gene.

show abstract

“…First, p.M59T is located in one of the WD repeats of CSA protein known to be involved in protein complex formation and other protein-protein interactions. The integrity of WD domains plays a key role in the biological functions of ERCC8/CSA protein as most of the reported mutations reside in these conserved domains [25]. ERCC8/CSA interacts with DDB1, Cullin 4A, and Roc1, and exhibits ubiquitin ligase activity in TC-NER [26].…”

Section: Discussionmentioning

confidence: 99%

A Novel Missense Mutation in ERCC8 Co-Segregates with Cerebellar Ataxia in a Consanguineous Pakistani Family

Gauhar

Tejwani

Abdullah

et al. 2022

Cells

View full text Add to dashboard Cite

Autosomal-recessive cerebellar ataxias (ARCAs) are heterogeneous rare disorders mainly affecting the cerebellum and manifest as movement disorders in children and young adults. To date, ARCA causing mutations have been identified in nearly 100 genes; however, they account for less than 50% of all cases. We studied a multiplex, consanguineous Pakistani family presenting with a slowly progressive gait ataxia, body imbalance, and dysarthria. Cerebellar atrophy was identified by magnetic resonance imaging of brain. Using whole exome sequencing, a novel homozygous missense mutation ERCC8:c.176T>C (p.M59T) was identified that co-segregated with the disease. Previous studies have identified homozygous mutations in ERCC8 as causal for Cockayne Syndrome type A (CSA), a UV light-sensitive syndrome, and several ARCAs. ERCC8 plays critical roles in the nucleotide excision repair complex. The p.M59T, a substitution mutation, is located in a highly conserved WD1 beta-transducin repeat motif. In silico modeling showed that the structure of this protein is significantly affected by the p.M59T mutation, likely impairing complex formation and protein-protein interactions. In cultured cells, the p.M59T mutation significantly lowered protein stability compared to wildtype ERCC8 protein. These findings expand the role of ERCC8 mutations in ARCAs and indicate that ERCC8-related mutations should be considered in the differential diagnosis of ARCAs.

show abstract

Identification of two novel homozygous nonsense mutations in TRAPPC9 in two unrelated consanguineous families with intellectual Disability from Iran

Cited by 10 publications

References 30 publications

TRAPPC9‐related neurodevelopmental disorder: Report of a homozygous deletion in TRAPPC9 due to paternal uniparental isodisomy

TRAPPC9‐related neurodevelopmental disorder: Report of a homozygous deletion in TRAPPC9 due to paternal uniparental isodisomy

TRAPPC9-Related Intellectual Disability: Report of Two New Cases and Review of the Literature

A Novel Missense Mutation in ERCC8 Co-Segregates with Cerebellar Ataxia in a Consanguineous Pakistani Family

Contact Info

Product

Resources

About