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

Abstract

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.

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

“…We show that the brain abnormalities identified in Trappc9 KO mice also result in behavioural deficits related to anxiety, cognition, learning and memory, which might reflect some the intellectual disability symptoms of human patients (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;Kramer et al, 2020;Mir et al, 2009;Mochida et al, 2009;Penon-Portmann et al, 2023;Philippe et al, 2009;Radenkovic et al, 2022). Our open field test data demonstrate an overall reduced locomotor activity of Trappc9 KO mice, which is consistent with recent findings from other Trappc9 mouse lines (Hu et al, 2023;Ke et al, 2020;Liang et al, 2020).…”

“…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).…”

Defective neurite elongation and branching in Nibp/Trappc9 deficient zebrafish and mice

“…Mutations in TRAPPC9 are associated with non-syndromic autosomal recessive intellectual disability (NS-ARID), assigned as "Intellectual Disability-Obesity-Brain Malformations-Facial Dysmorphism Syndrome" and "Intellectual developmental disorder, autosomal recessive 13" (OMIM #613192), and abbreviated as NIBP syndrome [24,28]. Loss-of-function TRAPPC9 mutations manifest microcephaly, intellectual disability, and obesity in patients [29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45]. Magnetic resonance imaging in affected individuals with NIBP syndrome has revealed reduced cerebral white matter volume with sulcal enlargement, thinning of the corpus callosum, and mild cerebellar volume loss [29][30][31].…”