Delineation of MidXq28‐duplication syndrome distal to MECP2 and proximal to RAB39B genes

Sinibaldi, Lorenzo; Parisi, Valentina; Lanciotti, Silvia; Fontana, Paolo; Kuechler, Alma; Baujat, Geneviève; Torres, Bárbara; Koetting, Judith; Splendiani, Alessandra; Postorivo, Diana; Beygo, Jasmin; Garaci, Francesco; Malan, Valérie; Lüdecke, Hermann‐Josef; Guida, Valentina; Krumbiegel, Mandy; Lonardo, Fortunato; Novelli, Antonio; Albrecht, Beate; Perria, C; Scarano, Gioacchino; Spielmann, Malte; Nardone, A.; Battaglia, Agatino; Brancati, Francesco; Bernardini, Laura

doi:10.1111/cge.13565

Cited by 6 publications

(13 citation statements)

References 16 publications

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“…First, spastic paralysis of both lower limbs starts around puberty, causing difficulty in climbing stairs and requiring surgical intervention. In R2 duplications, 6 of 15 cases (Vandewalle et al reported three of seven cases [ 8 ], Ward et al reported one of three cases [ 9 ], and Sinibald et al reported two of five cases [ 10 ]) exhibited pyramidal tract signs or spasticity (including a description of toe walking that required heel cord lengthening). R2 contains GDI1 .…”

Section: Discussionmentioning

confidence: 99%

“…Third, abnormalities in intracranial findings of the head, including microcephaly, are as follows: In R2 duplications, 11 of 15 cases (Vandewalle et al reported four of seven cases [ 8 ], Ward et al reported three of three cases [ 9 ], and Sinibald et al reported four of five cases [ 10 ]) presented with corpus callosum hypoplasia, and brainstem and cerebellar vermis hypoplasia with ventricular dilatation, suggesting that R2 duplications may cause dysgenesis of the brain during the embryonic period [ 18 ]. Yamamoto et al [ 7 ] and Honda et al [ 19 ] stated that duplication of the GDI1 region is associated with hypoplasia of the corpus callosum in patients.…”

Section: Discussionmentioning

confidence: 99%

“…Duplicated cases in the K/L-mediated Xq28 region (R2: region 2) [ 8 – 10 ] and the int22h1/int22h2-mediated Xq28 region (R3: region 3) [ 11 – 13 ], which are located distal to MECP2 and do not contain MECP2 , have recently been reported. In these case reports, hypotonia, susceptibility to infection, moderate-to-mild intellectual disability, psychiatric signs, and neurological signs were described.…”

Section: Introductionmentioning

confidence: 99%

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Duplication within two regions distal to MECP2: clinical similarity with MECP2 duplication syndrome

et al. 2023

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Background X-linked methyl-CpG-binding protein 2 (MECP2) duplication syndrome is prevalent in approximately 1% of X-linked intellectual disabilities. Accumulating evidence has suggested that MECP2 is the causative gene of MECP2 duplication syndrome. We report a case of a 17-year-old boy with a 1.2 Mb duplication distal to MECP2 on chromosome Xq28. Although this region does not contain MECP2, the clinical features and course of the boy are remarkably similar to those observed in MECP2 duplication syndrome. Recently, case reports have described duplication in the region distal to, and not containing, MECP2. These regions have been classified as the K/L-mediated Xq28 duplication region and int22h1/int22h2-mediated Xq28 duplication region. The case reports also described signs similar to those of MECP2 duplication syndrome. To the best of our knowledge, ours is the first case to include these two regions. Case presentation The boy presented with a mild to moderate regressive intellectual disability and progressive neurological disorder. He developed epilepsy at the age of 6 years and underwent a bilateral equinus foot surgery at 14 years of age because of the increasing spasticity in lower extremities since the age of 11. Intracranial findings showed hypoplasia of the corpus callosum, cerebellum, and brain stem; linear hyperintensity in the deep white matter; and decreased white matter capacity. During his childhood, he suffered from recurrent infection. However, genital problems, skin abnormalities and gastrointestinal manifestations (gastroesophageal reflux) were not observed. Conclusions Cases in which duplication was observed in the region of Xq28 that does not include MECP2 also showed symptoms similar to those of MECP2 duplication syndrome. We compared four pathologies: MECP2 duplication syndrome with minimal regions, duplication within the two distal regions without MECP2, and our case including both regions. Our results suggest that MECP2 alone may not explain all symptoms of duplication in the distal part of Xq28.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Duplication within two regions distal to MECP2: clinical similarity with MECP2 duplication syndrome

et al. 2023

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“…It has been suggested that Xq28 duplications involving the ID-associated filamin A gene ( FLNA ; 300017) contribute to the presence of chronic constipation [ 17 ], as FLNA point mutations have been found in families with pseudointestinal obstruction [ 128 , 129 ]. Against this hypothesis is that constipation was not a feature in recent case studies on patients harbouring a Xq28 duplication involving FLNA without MECP2 [ 42 , 63 , 130 , 131 ]. The presence of Hirschsprung disease in MDS, although rare, has also been suggested to be linked to dysregulated levels of the L1CAM gene (which can be implicated in Xq28 duplications) as L1CAM mutations have been detected in patients with X-linked hydrocephalus with Hirschsprung disease [ 22 , 132 , 133 ].…”

Section: The Syndromic Phenotype Of Mecp2 Duplicat...mentioning

confidence: 99%

A brief history of MECP2 duplication syndrome: 20-years of clinical understanding

Downs

Baynam

et al. 2022

Orphanet J Rare Dis

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MECP2 duplication syndrome (MDS) is a rare, X-linked, neurodevelopmental disorder caused by a duplication of the methyl-CpG-binding protein 2 (MECP2) gene—a gene in which loss-of-function mutations lead to Rett syndrome (RTT). MDS has an estimated live birth prevalence in males of 1/150,000. The key features of MDS include intellectual disability, developmental delay, hypotonia, seizures, recurrent respiratory infections, gastrointestinal problems, behavioural features of autism and dysmorphic features—although these comorbidities are not yet understood with sufficient granularity. This review has covered the past two decades of MDS case studies and series since the discovery of the disorder in 1999. After comprehensively reviewing the reported characteristics, this review has identified areas of limited knowledge that we recommend may be addressed by better phenotyping this disorder through an international data collection. This endeavour would also serve to delineate the clinical overlap between MDS and RTT.

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“…It was recently found that for individual with MDS, a larger duplication size correlates with greater phenotype severity, and greater phenotype severity was associated with the inclusion of RAB39B duplication (Peters et al, 2019). Interestingly, duplications occurring distal to MECP2 and proximal to RAB39B , termed MidXq28‐duplication syndrome, are also presented with features such as ID, epilepsy, brain malformations including microcephaly and minor craniofacial features (Sinibaldi et al, 2019). Duplication of genes other than MeCP2 and RAB39B , including those encoding FLNA, RPL10, and GDI1 located in this region, could therefore also contribute to MDS phenotypes.…”

Section: Introductionmentioning

confidence: 99%

RAB39B's role in membrane traffic, autophagy, and associated neuropathology

Tang

2020

Journal Cellular Physiology

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Neuropathological disorders are increasingly associated with dysfunctions in neuronal membrane traffic and autophagy, with defects among members of the Rab family of small GTPases implicated. Mutations in the human Xq28 localized gene RAB39B have been associated with X-linked neurodevelopmental defects including macrocephaly, intellectual disability, autism spectrum disorder (ASD), as well as rare cases of early-onset Parkinson's disease (PD). Despite the finding that RAB39B regulates GluA2 trafficking and could thus influence synaptic α-amino-3-hydroxy-5methyl-4-isoxazolepropionic acid receptor subunit composition, reasons for the wide-ranging neuropathological consequences associated with RAB39B defects have been unclear. Recent studies have now unraveled possible mechanisms underlying the neuropathological roles of this brain-enriched small GTPase. Studies in RAB39B knockout mice showed that RAB39B interacts with components of Class I phosphatidylinositol-3-kinase (PI3K) signaling. In its absence, the PI3K-AKTmechanistic target of rapamycin signaling pathway in neural progenitor cells (NPCs) is hyperactivated, which promotes NPC proliferation, leading to macrocephaly and ASD. Pertaining to early-onset PD, a complex of C9orf72, Smith-Magenis syndrome chromosome region candidate 8 and WD repeat domain 41 that functions in autophagy has been identified as a guanine nucleotide exchange factor of RAB39B. Here, recent findings that have shed light on our mechanistic understanding of RAB39B's role in neurodevelopmental and neurodegenerative pathologies are reviewed. Caveats and unanswered questions are also discussed, and future perspectives outlined.

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Delineation of MidXq28‐duplication syndrome distal to MECP2 and proximal to RAB39B genes

Cited by 6 publications

References 16 publications

Duplication within two regions distal to MECP2: clinical similarity with MECP2 duplication syndrome

Duplication within two regions distal to MECP2: clinical similarity with MECP2 duplication syndrome

A brief history of MECP2 duplication syndrome: 20-years of clinical understanding

RAB39B's role in membrane traffic, autophagy, and associated neuropathology

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