Olfactory Receptor-Related Duplicons Mediate a Microdeletion at 11q13.2q13.4 Associated with a Syndromic Phenotype

Wischmeijer, Anita; Magini, Pamela; Giorda, Roberto; Gnoli, Maria; Ciccone, Roberto; Cecconi, I; Franzoni, Emilio; Mazzanti, Laura; Romeo, G.; Zuffardi, Orsetta; Seri, Marco

doi:10.1159/000322054

Cited by 31 publications

(32 citation statements)

References 61 publications

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“…Specifically, cases 6319-3 and AU038-3 had mild axial hypotonia, oral dyspraxia and minor signs or cerebellar dysfunction (including dysmetry and dysdiadochokinesis). These clinical signs are unspecific, but were also reported in patients with ASD with more complex chromosomal rearrangements encompassing SHANK2 [33]. The individual carrying the de novo truncating mutation R841X (SK 0441-003) had a normal IQ and diagnosed with ASD without any developmental delays or dysmorphic features.…”

Section: Resultsmentioning

confidence: 99%

Meta-analysis of SHANK Mutations in Autism Spectrum Disorders: A Gradient of Severity in Cognitive Impairments

et al. 2014

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SHANK genes code for scaffold proteins located at the post-synaptic density of glutamatergic synapses. In neurons, SHANK2 and SHANK3 have a positive effect on the induction and maturation of dendritic spines, whereas SHANK1 induces the enlargement of spine heads. Mutations in SHANK genes have been associated with autism spectrum disorders (ASD), but their prevalence and clinical relevance remain to be determined. Here, we performed a new screen and a meta-analysis of SHANK copy-number and coding-sequence variants in ASD. Copy-number variants were analyzed in 5,657 patients and 19,163 controls, coding-sequence variants were ascertained in 760 to 2,147 patients and 492 to 1,090 controls (depending on the gene), and, individuals carrying de novo or truncating SHANK mutations underwent an extensive clinical investigation. Copy-number variants and truncating mutations in SHANK genes were present in ∼1% of patients with ASD: mutations in SHANK1 were rare (0.04%) and present in males with normal IQ and autism; mutations in SHANK2 were present in 0.17% of patients with ASD and mild intellectual disability; mutations in SHANK3 were present in 0.69% of patients with ASD and up to 2.12% of the cases with moderate to profound intellectual disability. In summary, mutations of the SHANK genes were detected in the whole spectrum of autism with a gradient of severity in cognitive impairment. Given the rare frequency of SHANK1 and SHANK2 deleterious mutations, the clinical relevance of these genes remains to be ascertained. In contrast, the frequency and the penetrance of SHANK3 mutations in individuals with ASD and intellectual disability—more than 1 in 50—warrant its consideration for mutation screening in clinical practice.

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Section: Resultsmentioning

confidence: 99%

Meta-analysis of SHANK Mutations in Autism Spectrum Disorders: A Gradient of Severity in Cognitive Impairments

et al. 2014

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“…A group of seven patients with ASD and ID (one of them presenting with ID only) were also carriers of rare nonsynonymous mutations predicted as deleterious, but inherited from an unaffected parent. Five independent studies then reported additional de novo heterozygous SHANK2 deletions in patients with ASD, speech, and developmental delay, and moderate ID (Pinto et al, ; Wischmeijer et al, ; Leblond et al, ; Schluth‐Bolard et al, ; Chilian et al, ). Leblond et al also observed an enrichment of mutations affecting conserved amino acids and altering synapse density in patients with ASD (Leblond et al, ).…”

Section: Shank and Autism Spectrum Disordersmentioning

confidence: 99%

The emerging role of SHANK genes in neuropsychiatric disorders

Guilmatre

Huguet

Delorme

et al. 2013

Developmental Neurobiology

229

174

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The genetic heterogeneity of neuropsychiatric disorders is high, but some pathways emerged, notably synaptic functioning. A large number of mutations have been described in genes such as neuroligins, neurexins, and SHANK that play a role in the formation and the maintenance of synapses. This review focuses on the disorders associated with mutations in SHANK3 and the other members of its family, SHANK1 and SHANK2. SHANKs are scaffolding proteins of the postsynaptic density of glutamatergic synapses. SHANK3 has been described in the Phelan-McDermid syndrome (PMS), but also in autism spectrum disorders (ASD) and schizophrenia associated to moderate to severe intellectual disability (ID) and poor language. The evolution of patients with PMS includes symptoms of bipolar disorder and regression. SHANK2 has been identified in patients with ASD with mild to severe ID. SHANK1 has been associated with high-functioning autism in male patients, while carrier females only display anxiety and shyness. Finally, based on neuropathological findings in animal models and patients, a possible role of SHANK in Alzheimer's disease is discussed. Altogether, this review describes the clinical trajectories associated with different mutations of the SHANK genes and provides information to further investigate the role of the SHANK genes in neuropsychiatric disorders.

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“…Patient 2389 carried a smaller, completely overlapping deletion spanning from 68.072 to 70.307 Mb and had congenital deafness. Patient 251808 had a much smaller deletion between 67.644 and 68.044 Mb and presented clinical features including low-set ears, down-slanting palpebral fissures, speech delay, and mental retardation14).…”

Section: Discussionmentioning

confidence: 99%

“…Wischmeijer et al14) reported the identification of a cryptic interstitial deletion (3.4 Mb) in chromosome 11q13.2-q13.4 that spans from 67.525 to 70.964 Mb in a child. The child was diagnosed with developmental delay, severe speech delay, moderate/severe mental retardation, and some dysmorphic features.…”

Section: Discussionmentioning

confidence: 99%

“…SHANK2 is a member of a family of genes (comprising of SHANK1 , SHANK2 , and SHANK3 ) encoding scaffold proteins. These genes are localized in the postsynaptic density of the excitatory synapses in the brain1415). Berkel et al15) identified SHANK2 loss-of function mutations in patients with autism spectrum disorder and mental retardation and suggested a potential role of this gene in the described pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

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Chromosome 11q13 deletion syndrome

Kim

Byeon

et al. 2016

Korean J Pediatr

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Chromosome 11q13 deletion syndrome has been previously reported as either otodental syndrome or oculo-oto-dental syndrome. The otodental syndrome is characterized by dental abnormalities and high-frequency sensorineural hearing loss, and by ocular coloboma in some cases. The underlying genetic defect causing otodental syndrome is a hemizygous microdeletion involving the FGF3 gene on chromosome 11q13.3. Recently, a new form of severe deafness, microtia (small ear) and small teeth, without the appearance of eye abnormalities, was also reported. In this report, we describe a 1-year-old girl presenting with ptosis of the left upper eyelid, right auricular deformity, high-arched palate, delayed dentition, simian line on the right hand, microcephaly, and developmental delay. In this patient, we identified a deletion in the chromosome 11q13.2-q13.3 (2.75 Mb) region by using an array-comparative genomic hybridization analysis. The deletion in chromosome 11q13 results in a syndrome characterized by variable clinical manifestations. Some of these manifestations involve craniofacial dysmorphology and require a functional workup for hearing, ophthalmic examinations, and long-term dental care.

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Olfactory Receptor-Related Duplicons Mediate a Microdeletion at 11q13.2q13.4 Associated with a Syndromic Phenotype

Cited by 31 publications

References 61 publications

Meta-analysis of SHANK Mutations in Autism Spectrum Disorders: A Gradient of Severity in Cognitive Impairments

Meta-analysis of SHANK Mutations in Autism Spectrum Disorders: A Gradient of Severity in Cognitive Impairments

The emerging role of SHANK genes in neuropsychiatric disorders

Chromosome 11q13 deletion syndrome

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