Balkan Journal of Medical Genetics

A 9-YEAR-OLD-GIRL WITH PHELAN McDERMID SYNDROME, WHO HAD BEEN DIAGNOSED WITH AN AUTISM SPECTRUM DISORDER
Görker I, Gürkan H, Demir Ulusal S, Atlı E, Ikbal Atlı E
*Corresponding Author: Işık Görker, Child and Adolescent Psychiatry Department, Trakya University, Faculty of Medicine, Balkan Yerleskesi, 22030, Edirne, Turkey. Tel: +90-532-355-9277. Fax: +90-284-435-7652. E-mail: isikgorker@gmail.com
page: 85

DISCUSSION

The genetic analyses of our patient showed that the 22q13.3 deletions leading to the loss of a functional copy of SHANK3 caused PHMDS. She has neurodevelopmental delay, mild intellectual disability assessed clinically, speech problems, behavior problems and minor dysmorphic features, as defined in references of PHMDS. SHANK3 remained a candidate gene as its expression is found in many regions of the brain, and the protein encoded is localized to the postsynaptic density, where it binds with other proteins that help maintain structural integrity. It is expressed at low levels in all brain regions during early postnatal development; peak expression correlates with a significant increase in synaptogenesis and synaptic maturation [3]. SHANK3, located on chromosome 22q13.3, is predominantly expressed in the cerebral cortex and cerebellum, and it is localized at excitatory synapses where it binds to neuroligins in post-synaptic boutons. It contains multiple protein-protein interaction domains and functions. As for neuroligins, several studies reported rare mutations or genomic deletion encompassing the SHANK3 locus in as many as 0.85% of all ASD individuals [4]. SHANK proteins are master scaffolding proteins of the synaptic density of glutamatergic synapses and are critical determinants of glutamate transmission and spine dynamics. Loss of a functional copy of SHANK3 accounts for about 0.5% of the cases of ASD and/or developmental delay, and there is likely wider role for SHANK3 and glutamate signalling abnormalities in ASD and related neuro-developmental disorders [5]. Soorya et al. [6] evaluated ASD in a sample of 32 patients with SHANK3 haploinsufficiency and showed that 84.0% met the criteria for ASD, including 75.0% meeting autism criteria. These findings indicate that PHMDS is one of the more highly penetrant causes of autism [2]. The high prevalence of ASD in PHMDS has led to further investigation of the role of SHANK3 in ASD and its potential overlap with other known genetic causes of ASD. Approximately 20.0% of ASD has been associated with specific chromosomal rearrangements, and more than 100 genes have been implicated. There is significant overlap in cellular dysfunction underlying many genetic subtypes of ASD, including deficits in synaptic function, synaptic plasticity, and excitatory glutamatergic signal transmission. Therefore, ASD has been hypothesized to occur as a result of synaptic dysregulation due to hypo- or hyper-connectivity, depending on the genetic insult and the role of affected proteins. As technology has progressed, increasingly sophisticated and higher resolution genetic analyses have allowed for greater detection of 22q13 deletions and SHANK3 mutations. Improved access to, and greater appreciation of the need for genetic testing, will inevitably lead to increased diagnosis of PHMDS in cases of ASD, intellectual disability, and developmental delay [3]. Duplication of 8p is a rare euchromatic variant, and some overlapping variations are associated with different phenotypes (severe, mild and unaffected) [7]. It has been reported in the literature that duplications of the 8p23.1 region have not a distinct effect on the phenotype [8,9]. However, Kennedy et al. [10] reported a 16-year-old girl with an 8p23.1 duplication who has a normal development but has congenital heart disease. Glancy et al. [7] suggested that an increased copy number of the MCPH1 gene, located in a duplicated locus between 8p23.1-8p23.2 [6.47 Mb between 3,848,594 and 10,323,426 bp] was associated with speech delay, ASD and learning deficits [7]. Although we found a gain of 1,399,992 bp on the 8p23.2 locus in our patient, the duplicated segment was not included in the MCPH1 gene. Thus, we conclude that the mild intellectual disability finding in our patient was because of the deleted 22q region. To the best of our knowledge, this is the first case reported to have a 22q deletion and 8p23.2 duplication. Declaration of Interest. The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.

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