A novel RAB39B mutation and concurrent de novo NF1 mutation in a boy with neurofibromatosis type 1, intellectual disability, and autism: a case report

Abstract

Background: Mutations in RAB39B at Xq28 causes a rare form of X-linked intellectual disability (ID) and Parkinson's disease. Neurofibromatosis type 1 (NF1) is caused by heterozygous mutations in NF1 occurring de novo in about 50% of cases, usually due to paternal gonadal mutations. This case report describes clinical and genetic findings in a boy with the occurrence of two distinct causative mutations in NF1 and RAB39B explaining the observed phenotype. Case presentation: Here we report a 7-year-old boy with multiple café-au-lait macules (CALMs) and freckling, severe macrocephaly, peculiar facial gestalt, severe ID with absent speech, epilepsy, autistic traits, self-harming, and aggressiveness. Proband is an only child born to a father aged 47. Parents did not present signs of NF1, while a maternal uncle showed severe ID, epilepsy, and tremors.By RNA analysis of NF1, we identified a de novo splicing variant (NM_000267.3:c.6579+2T>C) in proband, which explained NF1 clinical features but not the severe ID, behavioral problems, and aggressiveness. Family history suggested an X-linked condition and massively parallel sequencing of X-exome identified a novel RAB39B mutation (NM_171998.2:c.436_447del) in proband, his mother, and affected maternal uncle, subsequently validated by Sanger sequencing in these and other family members. Conclusions: The case presented here highlights how concurrent genetic defects should be considered in NF1 patients when NF1 mutations cannot reasonably explain all the observed clinical features.

RAB39B Deficiency Impairs Learning and Memory Partially Through Compromising Autophagy

“…As an evolutionarily conserved vesicle transporter regulator group, Rab proteins localize to different membrane structures to regulate vesicle trafficking ( Corbeel and Freson, 2008 ). Recent studies have found that loss-of-function RAB39B mutations are associated with various diseases including XLID, autistic spectrum disorder (ASD), and Parkinson’s disease (PD) ( Supplementary Table 1 ; Giannandrea et al, 2010 ; Mata et al, 2015 ; Guldner et al, 2016 ; Lesage et al, 2016 ; Shi et al, 2016 ; Ciammola et al, 2017 ; Woodbury-Smith et al, 2017 ; Santoro et al, 2020 ). However, the physiological functions of RAB39B as well as its pathological roles in disease pathogenesis remain largely elusive.…”

Whole-Exome Sequencing for Identifying Genetic Causes of Intellectual Developmental Disorders

“…These variants lead to different changes in DNA methylation patterns, which may provide a link between chromatin remodeling, DNA methylation, and gene expression during development. RAB39B 17 encodes the Rab family. Rab proteins are small GTPases involved in vesicle transport.…”

Non-Oncological Neuroradiological Manifestations in NF1 and Their Clinical Implications

“…A significant volume increase is observed in midline structures, with particular reference to the corpus callosum which looks altered both in terms of micro- and macro-structural measurements [ 37 , 40 ]. Subcortical structures, such as the hippocampus, amygdala and basal ganglia (i.e., thalamus and striatum), can also present larger volumes than normal [ 23 , 41 , 42 , 43 , 44 ]. Conversely, grey matter density is lower in the frontal parietal and temporal lobes (and, to a lesser extent, in cingulate and insular regions) with simplified cortical gyration and abnormal cortical thickness that decreases with age [ 18 , 23 , 45 , 46 ].…”

“…Symptoms are usually represented by acute-onset focal neurological deficits with sudden weakness or numbness in the face, arm or leg on one side; other possible manifestations also include headaches, visual disturbances, developmental delay and seizures [ 76 ]. Among phakomatoses, NF1 has been suggested as a possible MMS predisposing disorder, and few susceptibility genetic loci have been recently identified [ 43 , 77 ]. This is why, despite the fact that MMS was usually described as a consequence of cranial radiation therapy for NF1-related optic pathway glioma, the majority of cases have been reported as a primary manifestation of NF1 even in the absence of previous radiotherapy [ 71 , 78 ].…”