Submicroscopic deletion in 7q31 encompassing <i>CADPS2</i> and <i>TSPAN12</i> in a child with autism spectrum disorder and PHPV

Okamoto, Nobuhiko; Hatsukawa, Yoshikazu; Shimojima, Keiko; Yamamoto, Toshiyuki

doi:10.1002/ajmg.a.34028

Cited by 23 publications

(19 citation statements)

References 30 publications

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“…Haploinsufficiency of CADPS2 and TSPAN12 genes in the 7q31.31 region has been shown to contribute to ASD and PHPV, respectively. The patient in our study with the 7q31.3-q33 deletion shared similar phenotypes with this previously reported case, 6 such as dysmorphic facial features and developmental delays. However, ASD-related features were not significant in our patient because he suffered from more complicated symptoms such as heart failure and did not survive long enough to fully dissect the scope of his symptoms.…”

Section: Discussionsupporting

confidence: 72%

“…Another report of a patient confirmed with a 5.4-Mb deletion in the 7q31.31 region had congenital nystagmus due to bilateral persistent hyperplastic primary vitreous (PHPV), which phenotypically overlaps with FEVR. 6 However, this patient was determined to not have FEVR. He had dysmorphic facial features such as low set ears and developmental delays, which led to an autism spectrum disorder (ASD) diagnosis.…”

Section: Discussionmentioning

confidence: 99%

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Large Deletions of TSPAN12 Cause Familial Exudative Vitreoretinopathy (FEVR)

Seo

Kim

Park

et al. 2016

Invest. Ophthalmol. Vis. Sci.

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METHODS. Thirty-three Korean FEVR patients, who previously screened negative for TSPAN12 mutations, mutations in other FEVR-associated genes such as NDP, FZD4, LRP5, and large deletions and duplications of NDP, FZD4, and LRP5, were selected for TSPAN12 large deletion and duplication analyses. Semiquantitative multiplex PCR for TSPAN12 gene dosage analyses were performed, followed by droplet digital PCR (ddPCR) for validation. RESULTS.Among the 33 patients, three patients were confirmed to carry large TSPAN12 deletions. Two of them had whole-gene deletions of TSPAN12, and the other patient possessed a deletion of TSPAN12 in exon 4. FEVR severity detected in these patients was not more severe than in a patient with TSPAN12 point mutation.CONCLUSIONS. Regarding previously reported proportions of FEVR-associated genes contributing to the disorder's autosomal dominant inheritance pattern in Korea, we determined that patients with TSPAN12 large deletions were more common than patients with single nucleotide variants in TSPAN12. Evaluating TSPAN12 large deletions and duplications should be considered in FEVR screening and diagnosis as well as in routine genetic workups for FEVR patients.Keywords: familial exudative vitreoretinopathy, TSPAN12, large deletions, droplet digital PCR F amilial exudative vitreoretinopathy (FEVR) is a rare, genetically heterogeneous disorder that impairs vision and causes retinal detachment. Autosomal dominant inheritance is the most common form of FEVR and is known to be associated with the FZD4, LRP5, and TSPAN12 genes. Recently, the ZNF408 and KIF11 genes were also implicated in FEVR. 1,2 In a previous report by our group, mutational studies regarding FZD4, LRP5, and TSPAN12 were carried out in 51 unrelated FEVR patients lacking NDP mutations. Among them, mutations with high probabilities of being pathogenic were detected in 18 patients. 3 FZD4 mutations accounted for the largest proportion of autosomal dominant FEVR cases (13/18 patients, 72.2%), followed by LRP5 (4/18 patients, 22.2%), and TSPAN12 (1/18 patients, 5.6%) mutations. In rest of the 33 patients, no FZD4, LRP5, and TSPAN12 mutations were detected.In our previous report, large deletions/duplications in NDP, FZD4, and LRP5 had been screened via multiplex ligationdependent probe amplification (MLPA) using the SALSA P285-C1 LRP5-NDP-FZD4 (MRC-Holland, Amsterdam, Netherlands).Because TSPAN12 was not included, we looked for large deletions/duplications of TSPAN12 in the patients with no mutation detected to determine the genetic cause of FEVR. Gene dosage analysis by semiquantitative multiplex PCR and droplet digital PCR (ddPCR) were performed. In this study, we discovered and confirmed three cases of FEVR due to TSPAN12 large deletions. METHODS SubjectsAmong the 51 FEVR patients from our previous study, 33 patients were selected for large deletion/duplication analyses of TSPAN12. These patients were diagnosed with FEVR between

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Section: Discussionsupporting

confidence: 72%

Section: Discussionmentioning

confidence: 99%

Large Deletions of TSPAN12 Cause Familial Exudative Vitreoretinopathy (FEVR)

Seo

Kim

Park

et al. 2016

Invest. Ophthalmol. Vis. Sci.

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“…Moreover, we demonstrated that neurons with increased expression of dex3 fail to properly coordinate local BDNF release from axons [14], [15]. In addition, the association of CAPS2 with autism has been suggested not only by the presence of copy number variations in the CAPS2 gene in autistic patients [17]–[19], but also by decreased transcription of CAPS2 in the brains of people with autism [20]. Recently, it was also reported that CAPS2 deletion and missense mutations of maternal origin contribute to onset [21].…”

Section: Introductionmentioning

confidence: 84%

Axonal Localization of Ca2+-Dependent Activator Protein for Secretion 2 Is Critical for Subcellular Locality of Brain-Derived Neurotrophic Factor and Neurotrophin-3 Release Affecting Proper Development of Postnatal Mouse Cerebellum

et al. 2014

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Ca2+-dependent activator protein for secretion 2 (CAPS2) is a protein that is essential for enhanced release of brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) from cerebellar granule cells. We previously identified dex3, a rare alternative splice variant of CAPS2, which is overrepresented in patients with autism and is missing an exon 3 critical for axonal localization. We recently reported that a mouse model CAPS2Δex3/Δex3 expressing dex3 showed autistic-like behavioral phenotypes including impaired social interaction and cognition and increased anxiety in an unfamiliar environment. Here, we verified impairment in axonal, but not somato-dendritic, localization of dex3 protein in cerebellar granule cells and demonstrated cellular and physiological phenotypes in postnatal cerebellum of CAPS2Δex3/Δex3 mice. Interestingly, both BDNF and NT-3 were markedly reduced in axons of cerebellar granule cells, resulting in a significant decrease in their release. As a result, dex3 mice showed developmental deficits in dendritic arborization of Purkinje cells, vermian lobulation and fissurization, and granule cell precursor proliferation. Paired-pulse facilitation at parallel fiber-Purkinje cell synapses was also impaired. Together, our results indicate that CAPS2 plays an important role in subcellular locality (axonal vs. somato-dendritic) of enhanced BDNF and NT-3 release, which is indispensable for proper development of postnatal cerebellum.

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“…Quite recently a submicroscopic deletion of 5.4 Mb size was detected in a three-year-old boy with autism spectrum disorder that encompassed just 20 genes [65]. These 20 genes included the autism-candidate genes, CADPS2 and TSPAN12 , but also the receptor tyrosine phosphatase, RPTP β/ζ ( PTPRZ1 ).…”

Section: Overview Of Mutations In Wnt Pathway In Patients With Asd (Pmentioning

confidence: 99%

A review of the evidence for the canonical Wnt pathway in autism spectrum disorders

2012

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Microdeletion and microduplication copy number variations are found in patients with autism spectrum disorder and in a number of cases they include genes that are involved in the canonical Wnt signaling pathway (for example, FZD9, BCL9 or CDH8). Association studies investigating WNT2, DISC1, MET, DOCK4 or AHI1 also provide evidence that the canonical Wnt pathway might be affected in autism. Prenatal medication with sodium-valproate or antidepressant drugs increases autism risk. In animal studies, it has been found that these medications promote Wnt signaling, including among others an increase in Wnt2 gene expression. Notably, the available genetic information indicates that not only canonical Wnt pathway activation, but also inhibition seems to increase autism risk. The canonical Wnt pathway plays a role in dendrite growth and suboptimal activity negatively affects the dendritic arbor. In principle, this provides a logical explanation as to why both hypo- and hyperactivity may generate a similar set of behavioral and cognitive symptoms. However, without a validated biomarker to stratify for deviant canonical Wnt pathway activity, it is probably too dangerous to treat patients with compounds that modify pathway activity.

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Submicroscopic deletion in 7q31 encompassing CADPS2 and TSPAN12 in a child with autism spectrum disorder and PHPV

Cited by 23 publications

References 30 publications

Large Deletions of TSPAN12 Cause Familial Exudative Vitreoretinopathy (FEVR)

Large Deletions of TSPAN12 Cause Familial Exudative Vitreoretinopathy (FEVR)

Axonal Localization of Ca2+-Dependent Activator Protein for Secretion 2 Is Critical for Subcellular Locality of Brain-Derived Neurotrophic Factor and Neurotrophin-3 Release Affecting Proper Development of Postnatal Mouse Cerebellum

A review of the evidence for the canonical Wnt pathway in autism spectrum disorders

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