ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000022.10) (NC_000022.11)
Evidence for haploinsufficiency phenotype
PubMed ID Description
23758760 Soorya et al (2013) reported 22q13 deletions ranging in size from 101 kb to 8.45 Mb and including the gene SHANK3 in 30 individuals. Deletions were confirmed to be de novo in 23 cases. In 6 additional cases, three fathers and three mothers were studied, and did not carry SHANK3 deletions. All parents were healthy, suggesting a de novo origin.
21984749 Sarasua et al (2011) identified highly variable 22q13 deletions ranging from 0.22 to 9.22 Mb with no common breakpoints in 71 patients using a custom-designed high-resolution aCGH platform with a resolution of 100 bp. No inheritance information was available. The authors noted a correlation between increased deletion size and the severity of phenotypes in this cohort.
21779178 Bonaglia et al (2011) described 2 unrelated individuals with developmental delay, speech delay, facial dysmorphisms, and intellectual disability and heterozygous for deletions involving SHANK3. The first patient was a 23 year old female with a 73.8 kilobase deletion that removes exons 1-17 of SHANK3. The second patient was a 6 year old male with a 38.9 kilobase deletion that removes exons 1-9 of SHANK3.

Haploinsufficiency phenotype comments:

Deletions and loss-of-function mutations in SHANK3 are causative for the majority of clinical findings observed in 22q13.3 deletion syndrome (Phelan-McDermid syndrome). This syndrome is characterized by neonatal hypotonia, global developmental delay, absent to severely delayed speech, moderate to profound intellectual disability, normal to accelerated growth, autistic features, and additional variable findings. Patients with sequence-level mutations and intragenic deletions may have a less severe clinical presentation compared to patients with large, non-focal SHANK3 deletions. Additional relevant literature is summarized below: PMID 17173049: Durand et al (2007) describe 2 brothers with autism, severely impaired speech, and intellectual disability who are heterozygous for a 1-bp insertion in exon 21 of SHANK3. The insertion creates a frameshift and premature truncation of the protein. The mutation was not found in an unaffected brother or parents (de novo). PMID 20385823: Gauthier et al (2010) describe 3 brothers with schizophrenia and mild to moderate intellectual disability who are heterozygous for a de novo nonsense mutation in SHANK3, R1117X. This mutation was not found in 285 unaffected controls. PMID 20186804: Dhar et al. (2010) reported 13 patients with 22q13.33 deletions ranging from 95 kb to 8.5 Mb identified using 244K aCGH. No inheritance information was available. About 90 genes were deleted in the largest sized deletion, whereas the smallest deletion segment contained the three genes, SHANK3, ACR, and RABL2B. The authors discuss the phenotypic contribution of deleted genes (besides SHANK3), including ARSA (AR; metachromatic leukodystrophy), TYMP (AR; mitochondrial neuro-gastrointestinal encephalomyopathy), MLC1 (AR; megalencephalic leukoencephalopathy with subcortical cysts), ALG12 (congenital disorders of glycosylation 1g), and ATXN10 (AD; cerebellar ataxia). PMID: 11431708: Bonaglia et al (2001) describe a 4.5 year old boy with all the features of 22q13.3 deletion syndrome with a de novo balanced translocation between chromosomes 12 and 22. The breakpoints localize to chromosome 22 within exon 21 of SHANK3 and to chromosome 12 within an intron of APPL2. The translocation does not result in a loss of genetic material. The gene APPL2 is an effector of the small GTPase Rab5, which is involved in a signal transduction pathway required for cell proliferation. Although translocations do not count as primary evidence for dosage sensitivity scoring, this translocation involving SHANK3 provides additional supportive evidence for a role of SHANK3 in Phelan-McDermid syndrome.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

Triplosensitivity phenotype comment:

There are currently no reports of focal duplications involving only SHANK3, therefore the current triplosensitivity score is 0. Additional relevant literature is summarized below: PMID 24153177: Han et al (2013) describe two unrelated patients with hyperkinetic neuropsychicatric disorders and small 22q13 duplications involving SHANK3, identified by clinical exon-targeted aCGH testing. The first patient was an 11-year old girl with ADHD, seizures, hyperactivity, poor attention, auditory overstimulation, hyperphagia and kleptomania and a duplication ranging in size between 64 kb to 240 kb (uncertain if focal). The second patient was a 35-year old male with bipolar disorder and epilepsy and a duplication ranging in size between 115 kb and 302 kb (uncertain if focal). Inheritance information was unavailable. PMID 17975801: Okamoto et al (2007) described two unrelated patients with non-focal duplications in 22q13 including the gene SHANK3. Common clinical findings included infantile hypotonia, developmental delay and growth deficiency. Patient 1 had a de novo ~6 Mb duplication. Patient 2 showed a paternally inherited unbalanced translocation resulting in 17p deletion and 22q13 gain (>2 Mb) father: t(17;22)(p13;q13). See also additional reports of non-focal, larger 22q13 duplications: PMID 31254375 (Bitar et al 2019), PMID 27846046 (Chen et al 2017), PMID 17539913 (Failla et al 2007), PMID 17173049 (Durand et al 2007).