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. 2023 Aug 7;14(6):485–492. doi: 10.1159/000531439

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

Eyyup Uctepe a, Ahmet Yesilyurt b,c, Fatma Nisa Esen b, Sait Tumer b, Hanifenur Mancilar b, Fatma Mujgan Sonmez d,e,✉
PMCID: PMC10697769  PMID: 38058760

Abstract

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.

Keywords: Intellectual disability, Microcephaly, Autism, Exome sequencing, Array CGH, TRAPPC9

Introduction

Intellectual disability (ID) affects approximately 1–3% of the general population and is a major socioeconomic problem [Leonard and Wen, 2002]. It is one of the most common reasons for referral to the Child Neurology and Genetic Clinics. In countries such as Turkey where parental consanguinity is common, autosomal-recessive (AR) gene defects are the most common form of ID [Hoodfar and Teebi, 1996]. However, very little is revealed about causative genes and genotype-phenotype associations in AR-ID [Marangi et al., 2013]. It has been shown that AR-ID is highly heterogeneous and the vast majority of responsible genes for AR-ID are still unknown [Ropers, 2010]. Hence, only up to 60% of patients get a precise genetic diagnosis due to this genetic heterogeneity and the lack of specific phenotypic features [Gilissen et al., 2014].

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].

Here, we described two unrelated patients with ID, microcephaly, and autistic features, and identified three novel mutations in TRAPPC9. Also, we reviewed the clinical findings and mutation spectrum of the reported patients with TRAPPC9-related ID so far.

Methods

Patients and Ethics Statement

We ascertained probands from two different consanguineous Turkish families. We obtained a written informed consent from the families of the patients for participation in this study and accompanying images. The study was performed according to the Declaration of Helsinki protocols.

Karyotyping and Array CGH Analyses

Cytogenetic analysis was performed on GTG-banded chromosomes from circulating leukocytes using a standard protocol. Array CGH was performed using a 60-K whole-genome oligonucleotide microarray following the manufacturer’s protocol (Human Genome CGH Microarray, 60 K, Agilent Inc.).

Whole-Exome Sequencing Studies

Whole-exome sequencing (WES) was performed for case 2. Genomic DNA was extracted from peripheral blood leukocytes. Twist® Human Core Exome kit was used for enrichment. Libraries were sequenced on a NovaSeq 6000 platform (Illumina). The sequencing data were aligned to reference human genome assembly GRCh37 (hg19) using the Burrows-Wheeler Aligner (BWA-MEM) (Sentieon) [Li and Durbin, 2009]. Duplicate marking, indel realignment, base-quality recalibration, and variant calling were performed using GATK algorithms (Sentieon). Variant annotation, filtering, and interpretation were performed with VarSome Clinical platform (Saphetor). Variants in coding region, splice regions, and known pathogenic variants in noncoding regions were retained. Common variants with minor allele frequency >1% in Genome Aggregation Database (gnomAD) were filtered out. Filtering and prioritization of potential disease-causing variants were performed according to the mode of inheritance, status in ClinVar, HPO terms describing the patient’s phenotype, and in silico pathogenicity prediction. ACMG 2015 guideline was used for variant evaluation (8). The variants identified in this study were submitted to the Leiden Open Variation Database (LOVD) at www.lovd.nl/TRAPPC9.

Sanger Sequencing

All coding exons and flanking intronic sequences of TRAPPC9 gene were sequenced by Sanger sequencing for case 1. Parental segregation of the homozygous variant in case 2 was confirmed by Sanger sequencing.

Results

Case Reports

Case 1

Nine-year-old female patient was admitted to our clinic when she was 3.9 years old with complaints of microcephalia, mental and motor retardation. She was born with C/S to a consanguineous couple who are first-degree cousin family following uneventful gestation. The first gestation was D&C because of hydrocephalus (shown in Fig. 1). Her head circumference was 36 cm on the first day of life. Her head control was at 3 months of age, and she could sit without support at 7 months old, walked without support at 5 years old, and could only say 4–5 single words. At 2 years old, muscle biopsy was applied in another center because of high CK level (239 ng/L) and revealed nonspecific findings.

Fig. 1.

Fig. 1.

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Pedigrees of the patients with TRAPPC9 variants.

Physical examination at that time showed microcephaly (45 cm at admission), round face, full cheeks, thin upper lip, and ptosis (shown in Fig. 2). Neurological evaluation showed ID, microcephaly, motor retardation, and spasticity on the left ankle.

Fig. 2.

Fig. 2.

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Appearance of case 1 from the lateral and anterior view.

On laboratory investigation, hemogram, and biochemical analyses including liver and renal function tests, CK levels (116, 247, and 199 ng/L) were normal. Metabolic investigations were normal, including ammonium, lactic acid, urine and blood amino acids, urine organic acids, tandem MS, acylcarnitine, and homocysteine. ECHO, abdominal ultrasonography, and EEG were evaluated as normal. Brain MRI showed thinning of posterior body part of the corpus callosum and several areas of T2 hyperintensity in the periventricular white matter.

Now, she is 9 years old. She can speak only 15 single words. Furthermore, the family described some behavioral problems that started 4 years ago such as hyperactivity, frequent sleep awakenings, and some autistic features including stereotypic hand movements. At that time, laboratory investigation showed high CK level (263.6 ng/L ) and vitamin D deficiency (8.8 ng/L, N: 30–100).

Case 2

Eleven-year-old girl was admitted with autistic features and ID. She was the first child of consanguineous parents. She was born as the first child of the family following uneventful gestation and delivery. She had one healthy sister and one healthy brother. There was a history of autism, aggressive behavior, and obesity in a boy of her father’s uncle.

Her head control was at 2 months of age, and she could sit without support at 6 months old. She had normal mental and motor development until 7 months of age. At 7 months old, there was a seizure history following vaccination. She could crawl at 9 months. She could say her first words at 12 months. At the 15th month, the family noticed that the child still could not walk and add new words as well as inattentive behavior. She could walk at 25 months via physiotherapy. There are hand clapping movements beginning from infancy and arm biting behavior from 10 years old. At 11 years old, there was no significant dysmorphic feature on physical examination except microcephalia (her head circumference: 50 cm, <3p). Neurological examination showed autistic behavior such as stereotypic hand movements. She can speak with 15 single words and say sentences with two words. Currently, she is being followed in the pediatric endocrinology department for primary amenorrhea and increased hair growth on the arms and back.

On laboratory investigation, hemogram and biochemical analysis including liver and renal function tests were normal. ECHO, abdominal ultrasonography, and EEG were evaluated as normal. Brain MRI showed thin corpus callosum, widened lateral ventricles seconder to central cerebral atrophy, and periventricular ischemic white matter changes. Both the karyotype and microarray test results were normal.

Genetic Study Results

Case 1

Cytogenetic analysis showed a normal 46,XX karyotype for case 1. However, the array CGH analysis of the proband identified a 1.7-Mb heterozygous deletion on chromosome 8 (8q24.23-q24.3) encompassing the last 5 exons of TRAPPC9, KCNK9, COL22A1, and the first 6 exons of FAM135B gene (shown in Fig. 3a).

Fig. 3.

Fig. 3.

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a Results of array CGH analysis in case 1 (deleted region). b Schematic presentation of all reported TRAPPC9 variants (variants reported in this study are shown in squares).

Sanger sequencing for TRAPPC9 gene revealed one base pair deletion c.3435delG in the last exon of TRAPPC9 (NM_031466) predicting abolition of the stop codon p.(Thr1146Profs*8) (NP_113654) and addition of 6 amino acid residues at the C-terminus of the TRAPPC9 protein (shown in Fig. 3b).

Case 2

After variant prioritization in the WES data, we identified the homozygous missense variant c.623A>C (p.His208Pro) in exon 3 of TRAPPC9 (NM_031466.8). Sanger sequencing confirmed the homozygous status of c.623A>C variant in the proband, and targeted variant analysis showed both parents were heterozygous carrier for this variant (shown in Fig. 3b, 4). The histidine at codon 208 is moderately conserved, and there is a moderate physicochemical difference between histidine and proline. Individual computational analysis tools predict potential disrupting effect of this variant on protein structure and function (SIFT: damaging, PolyPhen-2: damaging); however, meta-scores such as REVEL and MetaLR are uncertain whether this variant is neutral or deleterious (REVEL: 0.50, MetaLR: 0.40). This missense change has not been observed in Genome Aggregation Database (gnomAD https://gnomad.broadinstitute.org/), Exome Variant Server (http://evs.gs.washington.edu/EVS/), 1000 Genomes (http://www.1000genomes.org/) population frequency databases. It is also not present in Acibadem Labgen in-house database. There were not any other candidate variants other than TRAPPC9 after variant prioritization according to inheritance pattern as autosomal dominant, AR, or X-linked.

Fig. 4.

Fig. 4.

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Electropherogram of the TRAPPC9 variant identified in case 2 and her parents.

Discussion

Here, we describe two Turkish patients with ID, microcephaly, and autistic features born to two unrelated consanguineous Turkish families. In this study, we report two novel point mutations (c.623A>C and c.3435delG) in TRAPPC9 and a 1.7-Mb-sized deletion on chromosome 8 (8q24.23-q24.3) including the last 5 exons of TRAPPC9 expanding allelic heterogeneity of this disease. 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. However, 20 cases with TRAPPC9-related ID from 5 families from Mediterranean countries have c.1423C>T (p. Arg475∗) mutation so far, which can be reputed as the founder mutation for this region [Mir et al., 2009; Mochida et al., 2009; Abou Jamra et al., 2011; Giorgio et al., 2016; Abbasi et al., 2017].

In addition to these small sequence variants, six copy number variations including our case (four microdeletions and two microduplications) have been reported in these patients highlighting the role of CNVs at this locus in the etiology of TRAPPC9-related ID [Koifman et al., 2010; Boonsawat et al., 2019; Alvarez-Mora et al., 2021]. The microdeletion in our case is 1.7 Mb in length and encompasses the last 5 exons of TRAPPC9, KCNK9, COL22A1, and the first 6 exons of FAM135B gene (Fig. 3a). To the best of our knowledge, this microdeletion is the largest deletion to be identified in patients with TRAPPC9-related ID.

Different types of pathogenic variants are associated with TRAPPC9-related ID. The majority of these variants result in nonfunctional TRAPPC9 proteins due to truncating nonsense, frameshift, or splice variants, and missense variants were only reported in a few cases [Duerinckx et al., 2018; Bai and Kong, 2019; Kramer et al., 2020; Alvarez-Mora et al., 2021]. Mir et al. [2009] and Philippe et al. [2009] demonstrated a significant degree of nonsense-mediated mRNA decay in homozygous patients with quantitative real-time PCR to support this prediction. In addition to this, Mochida et al. [2009] and Philippe et al. [2009] determined the almost complete absence of TRAPPC9 protein by Western blot analysis in the patients with TRAPPC9 mutations. The diverse phenotypic presentation of the reported patients suggests that the location of the pathogenic variants within TRAPPC9 may result in different phenotypes or the variants in the other genes may also contribute to the different phenotypic presentations of TRAPPC9 variants in these patients. There is currently no comprehensive study investigating the relationship between variant type, location, and the clinical presentation of patients.

The frameshift variant in the last exon of TRAPPC9 in case 1 expands the protein length and shows a similar effect to stop-loss variants. Stop-loss variants are a very rare but recognized mechanism of some genetic diseases, not previously reported in TRAPPC9 [Aslanger et al., 2022]. The downstream consequences of the stop-loss variant are unclear, but it could impact how the protein is folded, where it goes in the cell, or how it interacts with other molecules. We proposed that this stop-loss variant is the likely cause of disease in our patient because it shows phenotypic overlap, no other causative variant on other ID-related genes on WES analysis, and the gene is intolerant to haploinsufficient variants. Previously reported stop-loss pathogenic variants in different genes are generally associated with milder phenotypes compared to other loss of function variant types at the same gene [Spaull et al., 2022; van Wijck et al., 2023].

The TRAPPC9 mutation-associated phenotype was initially reported as a non-syndromic ID with postnatal microcephaly [Mir et al. 2009; Mochida et al. 2009; Philippe et al. 2009]. However, most recent reports have provided evidence that loss of TRAPPC9 function underlies a syndromic form of ID [Bai and Kong, 2019; Hnoonual et al., 2019; Wilton et al., 2020; Alvarez-Mora et al., 2021; Ben Ayed et al., 2021; Yousefipour et al., 2021; Aslangeret al., 2022; Radenkovic et al., 2022]. According to our current review of previous studies, most common clinical manifestations of mutations associated with TRAPPC9 were ID-DD (100%), microcephaly (91%), dysmorphic facial features (60%), obesity (44%), autistic features (42%), and brain abnormalities such as thin corpus callosum (90%), white matter signal abnormalities (91%), cerebral hypoplasia (72%), cerebellar hypoplasia (Table 1). Consistent with these reports, common findings in our cases were ID/DD, microcephaly, autistic behavior, and brain abnormalities such as thin corpus callosum and white matter signal abnormalities.

Table 1.

The clinical findings associated with patients with mutations in TRAPPC9 gene

Clinical features Current study Previous reports Total, n/N (%)
case 1 case 2
ID/DD + + 60/60 62/62 (100)
Microcephaly + + 50/55 52/57 (91)
Obesity − − 18/39 18/41 (44)
Autistic features + + 12/31 14/33 (42)
Seizure − + 7/44 8/46 (17)
Dysmorphic features + − 31/51 32/53 (60)
Cranial MRI abnormalities
Thin corpus callosum + + 26/29 28/31 (90)
Cerebral hypoplasia − + 17/23 18/25 (72)
Cerebellar hypoplasia − − 11/23 11/25 (44)
Abnormality signal of white matter + + 28/31 30/33 (91)
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Autistic features are very common in patients with TRAPPC9 mutations unlike the first reports with TRAPPC9, and both of our patients showed autistic features (Table 1). Bodnar et al. [2020] proposed that heterozygous loss of function variant of TRAPPC9 could increase ASD risk, which would be more increased in patients with biallelic mutations [Bodnar et al., 2020].

Dysmorphic features seen in about half of the patients are round face, full cheeks, prominent nasal bridge, prominent upper central incisors, thin superior lip, and short philtrum [Aslanger et al., 2022]. One of our 2 patients showed dysmorphic features.

Mir et al. [2009] reported a family including seven living and one deceased affected member with TRAPPC9 mutation that creatine phosphokinase levels (between 218 and 402 U/L) were elevated in three of them similar to case 1 in this study [Mir et al., 2009]. In conclusion, we described 2 cases with TRAPPC9-related ID and reviewed the clinical findings and mutation spectrum of the all patients reported so far. It is shown that the most consistent clinical findings for TRAPPC9-related ID are ID/DD, microcephaly, and brain MRI abnormalities such as thin corpus callosum and white matter signal changes. The mutations in TRAPPC9 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 the proper functioning of TRAPPC9.

Acknowledgments

We thank the patients and their families for participating in this study.

Statement of Ethics

The protocols used in this study were in compliance with the Declaration of Helsinki. Written informed consent was obtained from the parent/legal guardian of the patients for publication of the details of their medical case and any accompanying images. Informed consent for genetic analysis was obtained from the family in compliance with national ethics regulations. As so, ethical approval was not required for this study in accordance with local/national guidelines.

Conflict of Interest Statement

The authors declare that there are no potential conflicts of interest with respect to the authorship and/or publication of this manuscript.

Funding Sources

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Author Contributions

Eyyup Uctepe, Ahmet Yesilyurt, and Fatma Mujgan Sonmez examined the patients and made the clinical diagnosis. Fatma Nisa Esen, Hanife Mancilar, and Sait Tumer analyzed the whole-exome sequencing data and performed confirmatory sequencing studies. All authors contributed to the writing of the manuscript.

Funding Statement

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Data Availability Statement

All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.

References

  1. Abbasi AA, Blaesius K, Hu H, Latif Z, Picker-Minh S, Khan MN, et al. Identification of a novel homozygous TRAPPC9 gene mutation causing non-syndromic intellectual disability, speech disorder, and secondary microcephaly. Am J Med Genet B Neuropsychiatr Genet. 2017;174(8):839–45. 10.1002/ajmg.b.32602. [DOI] [PubMed] [Google Scholar]
  2. Abou Jamra R, Wohlfart S, Zweier M, Uebe S, Priebe L, Ekici A, et al. Homozygosity mapping in 64 Syrian consanguineous families with non-specific intellectual disability reveals 11 novel loci and high heterogeneity. Eur J Hum Genet. 2011;19(11):1161–6. 10.1038/ejhg.2011.98. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Alvarez-Mora MI, Corominas J, Gilissen C, Sanchez A, Madrigal I, Rodriguez-Revenga L. Novel compound heterozygous mutation in TRAPPC9 gene: the relevance of whole genome sequencing. Genes. 2021;12(4):557. 10.3390/genes12040557. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Aslanger AD, Goncu B, Duzenli OF, Yucesan E, Sengenc E, Yesil G. Biallelic loss of TRAPPC9 function links vesicle trafficking pathway to autosomal recessive intellectual disability. J Hum Genet. 2022;67(5):279–84. 10.1038/s10038-021-01007-8. [DOI] [PubMed] [Google Scholar]
  5. Bai Z, Kong X. [Diagnosis of a case with mental retardation due to novel compound heterozygous variants of TRAPPC9 gene]. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2019;36(11):1115–9. 10.3760/cma.j.issn.1003-9406.2019.11.015. [DOI] [PubMed] [Google Scholar]
  6. Ben Ayed I, Bouchaala W, Bouzid A, Feki W, Souissi A, Ben Nsir S, et al. Further insights into the spectrum phenotype of TRAPPC9 and CDK5RAP2 genes, segregating independently in a large Tunisian family with intellectual disability and microcephaly. Eur J Med Genet. 2021;64(12):104373. 10.1016/j.ejmg.2021.104373. [DOI] [PubMed] [Google Scholar]
  7. Bodnar B, DeGruttola A, Zhu Y, Lin Y, Zhang Y, Mo X, et al. Emerging role of NIK/IKK2-binding protein (NIBP)/trafficking protein particle complex 9 (TRAPPC9) in nervous system diseases. Transl Res. 2020;224:55–70. 10.1016/j.trsl.2020.05.001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Bolat H, Unsel-Bolat G, Derin H, Şen A, Ceylaner S. Distinct autism spectrum disorder phenotype and hand-flapping stereotypes: two siblings with novel homozygous mutation in TRAPPC9 gene and literature review. Mol Syndromol. 2022;13(4):263–9. 10.1159/000522041. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Boonsawat P, Joset P, Steindl K, Oneda B, Gogoll L, Azzarello-Burri S, et al. Elucidation of the phenotypic spectrum and genetic landscape in primary and secondary microcephaly. Genet Med. 2019;21(9):2043–58. 10.1038/s41436-019-0464-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Duerinckx S, Meuwissen M, Perazzolo C, Desmyter L, Pirson I, Abramowicz M. Phenotypes in siblings with homozygous mutations of TRAPPC9 and/or MCPH1 support a bifunctional model of MCPH1. Mol Genet Genomic Med. 2018;6(4):660–5. 10.1002/mgg3.400. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Gilissen C, Hehir-Kwa JY, Thung DT, van de Vorst M, van Bon BW, Willemsen MH, et al. Genome sequencing identifies major causes of severe intellectual disability. Nature. 2014;511(7509):344–7. 10.1038/nature13394. [DOI] [PubMed] [Google Scholar]
  12. Giorgio E, Ciolfi A, Biamino E, Caputo V, Di Gregorio E, Belligni EF, et al. Whole exome sequencing is necessary to clarify ID/DD cases with de novo copy number variants of uncertain significance: two proof-of-concept examples. Am J Med Genet A. 2016;170(7):1772–9. 10.1002/ajmg.a.37649. [DOI] [PubMed] [Google Scholar]
  13. Hnoonual A, Graidist P, Kritsaneepaiboon S, Limprasert P. Novel compound heterozygous mutations in the TRAPPC9 gene in two siblings with autism and intellectual disability. Front Genet. 2019;10:61. 10.3389/fgene.2019.00061. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Hoodfar E, Teebi AS. Genetic referrals of Middle Eastern origin in a western city: inbreeding and disease profile. J Med Genet. 1996;33(3):212–5. 10.1136/jmg.33.3.212. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Kakar N, Goebel I, Daud S, Nurnberg G, Agha N, Ahmad A, et al. A homozygous splice site mutation in TRAPPC9 causes intellectual disability and microcephaly. Eur J Med Genet. 2012;55(12):727–31. 10.1016/j.ejmg.2012.08.010. [DOI] [PubMed] [Google Scholar]
  16. Koifman A, Feigenbaum A, Bi W, Shaffer LG, Rosenfeld J, Blaser S, et al. A homozygous deletion of 8q24.3 including the NIBP gene associated with severe developmental delay, dysgenesis of the corpus callosum, and dysmorphic facial features. Am J Med Genet A. 2010;152A(5):1268–72. 10.1002/ajmg.a.33319. [DOI] [PubMed] [Google Scholar]
  17. Kramer J, Beer M, Bode H, Winter B. Two novel compound heterozygous mutations in the TRAPPC9 gene reveal a connection of non-syndromic intellectual disability and autism spectrum disorder. Front Genet. 2020;11:972. 10.3389/fgene.2020.00972. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Leonard H, Wen X. The epidemiology of mental retardation: challenges and opportunities in the new millennium. Ment Retard Dev Disabil Res Rev. 2002;8(3):117–34. 10.1002/mrdd.10031. [DOI] [PubMed] [Google Scholar]
  19. Li H, Durbin R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics. 2009;25(14):1754–60. 10.1093/bioinformatics/btp324. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Marangi G, Leuzzi V, Manti F, Lattante S, Orteschi D, Pecile V, et al. TRAPPC9-related autosomal recessive intellectual disability: report of a new mutation and clinical phenotype. Eur J Hum Genet. 2013;21(2):229–32. 10.1038/ejhg.2012.79. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Mir A, Kaufman L, Noor A, Motazacker MM, Jamil T, Azam M, et al. Identification of mutations in TRAPPC9, which encodes the NIK- and IKK-beta-binding protein, in nonsyndromic autosomal-recessive mental retardation. Am J Hum Genet. 2009;85(6):909–15. 10.1016/j.ajhg.2009.11.009. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Mochida GH, Mahajnah M, Hill AD, Basel-Vanagaite L, Gleason D, Hill RS, et al. A truncating mutation of TRAPPC9 is associated with autosomal-recessive intellectual disability and postnatal microcephaly. Am J Hum Genet. 2009;85(6):897–902. 10.1016/j.ajhg.2009.10.027. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Mortreux J, Busa T, Germain DP, Nadeau G, Puechberty J, Coubes C, et al. The role of CNVs in the etiology of rare autosomal recessive disorders: the example of TRAPPC9-associated intellectual disability. Eur J Hum Genet. 2018;26(1):143–8. 10.1038/s41431-017-0018-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Philippe O, Rio M, Carioux A, Plaza JM, Guigue P, Molinari F, et al. Combination of linkage mapping and microarray-expression analysis identifies NF-kappaB signaling defect as a cause of autosomal-recessive mental retardation. Am J Hum Genet. 2009;85(6):903–8. 10.1016/j.ajhg.2009.11.007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Radenkovic S, Martinelli D, Zhang Y, Preston GJ, Maiorana A, Terracciano A, et al. TRAPPC9-CDG: a novel congenital disorder of glycosylation with dysmorphic features and intellectual disability. Genet Med. 2022;24(4):894–904. 10.1016/j.gim.2021.12.012. [DOI] [PubMed] [Google Scholar]
  26. Ropers HH. Genetics of early onset cognitive impairment. Annu Rev Genomics Hum Genet. 2010;11:161–87. 10.1146/annurev-genom-082509-141640. [DOI] [PubMed] [Google Scholar]
  27. Spaull R, Steel D, Barwick K, Prabhakar P, Wakeling E, Kurian M. STXBP1 stop-loss mutation associated with complex early onset movement disorder without epilepsy. Mov Disord Clin Pract. 2022;43(1):837–40. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. van Wijck RTA, Swagemakers SMA, van der Spek PJ, van Hagen PM, van Daele PLA. A CDC42 stop-loss mutation in a patient with relapsing polychondritis and autoinflammation. J Clin Immunol. 2023;43(1):69–71. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Wilton KM, Gunderson LB, Hasadsri L, Wood CP, Schimmenti LA. Profound intellectual disability caused by homozygous TRAPPC9 pathogenic variant in a man from Malta. Mol Genet Genomic Med. 2020;8(5):e1211. 10.1002/mgg3.1211. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Yousefipour F, Mozhdehipanah H, Mahjoubi F. Identification of two novel homozygous nonsense mutations in TRAPPC9 in two unrelated consanguineous families with intellectual disability from Iran. Mol Genet Genomic Med. 2021;9(12):e1610. 10.1002/mgg3.1610. [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.

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