A novel RAB39B mutation and concurrent de novo NF1 mutation in a boy with neurofibromatosis type 1, intellectual disabil
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CASE REPORT
Open Access
A novel RAB39B mutation and concurrent de novo NF1 mutation in a boy with neurofibromatosis type 1, intellectual disability, and autism: a case report Claudia Santoro1,2, Teresa Giugliano3, Pia Bernardo4, Federica Palladino2, Annalaura Torella3, Francesca del Vecchio Blanco3, Maria Elena Onore3, Marco Carotenuto1, Vincenzo Nigro3,5 and Giulio Piluso3*
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. Keywords: Neurofibromatosis type 1, RAB39B, X-linked intellectual disability, Autism, Parkinson’s disease, Case report
Background Mutations in RAB39B (MIM 300774) at Xq28 cause a syndromic form of X-linked intellectual disability (XLID), with very few affected males described to date (MRX72; MIM 300271) [1–3].
* Correspondence: [email protected] 3 Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Via Luigi De Crecchio,7 –, 80138 Naples, Italy Full list of author information is available at the end of the article
Affected patients present variable neurological features, including moderate to severe ID, seizures, autism spectrum disorder (ASD), macrocephaly, delayed psychomotor development, and early-onset Parkinson’s disease, as in the allelic Waisman syndrome (WSMN; OMIM 311510) [2]. In mouse brain, Rab39b is expressed in cortical and hippocampal neurons, as well as in dopaminergic neurons of the substantia nigra, concordant with its association with parkinsonism and cognitive impairment
© The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribu
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