Further insights into the spectrum phenotype of TRAPPC9 and CDK5RAP2 genes, segregating independently in a large Tunisian family with intellectual disability and microcephaly

Microcephaly with a disproportionate hippocampal reduction, stem cell loss and neuronal lipid droplet symptoms inTrappc9KO mice

“…In this study, we demonstrate by using MRI that the microcephaly of Trappc9 KO mice has a postnatal onset and is clearly established at weaning age. These findings are in line with TRAPPC9 patient data, which show microcephaly within the first year of life (Amin et al, 2022; Aslanger et al, 2022; Ben Ayed et al, 2021; Bolat et al, 2022; Hnoonual et al, 2019; Koifman et al, 2010; Penon-Portmann et al, 2023; Radenkovic et al, 2022) as well as data from other recently published Trappc9 KO mouse studies, which reported differences at postnatal days 7, 15 and 20, but not at birth (Hu et al, 2023; Ke et al, 2020). Monogenic disorders causing postnatal-onset microcephaly are less common than those causing primary microcephaly, which are mostly due to cell proliferation defects during embryogenesis.…”

“…One of the most consistent symptoms of patients with TRAPPC9 mutations is microcephaly, which has been detected in children as early as one year of age and includes reduced white matter (e.g. corpus callosum), cerebral and cerebellar atrophies (Amin et al, 2022; Aslanger et al, 2022; Ben Ayed et al, 2021; Bolat et al, 2022; Hnoonual et al, 2019; Koifman et al, 2010; Penon-Portmann et al, 2023; Radenkovic et al, 2022). To investigate microcephaly in homozygous Trappc9 mutant mice, we determined brain volumes via MRI as well as tissue weights at birth, weaning and adult stages.…”

“…Microcephaly in these patients was detectable by Magnetic Resonance Imaging (MRI) within the first year of life and included grey matter atrophies as well as white matter reductions (e.g. corpus callosum) (Amin et al, 2022; Aslanger et al, 2022; Ben Ayed et al, 2021; Bolat et al, 2022; Hnoonual et al, 2019; Koifman et al, 2010; Penon-Portmann et al, 2023; Radenkovic et al, 2022). Other disease symptoms occur more variably with obesity, dysmorphic facial features and hand-flapping movements being described in approximately half the patients (Aslanger et al, 2022; Bolat et al, 2022; Kramer et al, 2020).…”

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

“…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.…”

“…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).…”