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.
Journal Section:
Original Article
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
.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
.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
.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
.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
.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
.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
.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
.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.
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
.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
.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
.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
.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
.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
.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
.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
.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
.19.
Li
H
, Durbin
R
. Fast and accurate short read alignment with Burrows-Wheeler transform
. Bioinformatics
. 2009
;25
(14
):1754
–60
.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
.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
.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
.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
.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
.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
.26.
Ropers
HH
. Genetics of early onset cognitive impairment
. Annu Rev Genomics Hum Genet
. 2010
;11
:161
–87
.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
.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
.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
.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
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