The packet lists SHANK3, located on chromosome 22, as the known gene, with a ClinGen validity classification of DEFINITIVE. GeneReviews describes the cause as a deletion at 22q13.3 involving at least part of SHANK3, a pathogenic variant in SHANK3, or, rarely, a chromosomal rearrangement disrupting SHANK3, and states that some features appear due to heterozygous loss of SHANK3 alone while others are seen primarily with larger deletions that include adjacent genes. The packet lists sporadic and autosomal dominant inheritance patterns; GeneReviews describes the condition as autosomal dominant and most often caused by a de novo alteration. For deletions, it reports that some arise from an unbalanced structural rearrangement, about half of which involve a parent carrying a balanced translocation, that some arise from a ring chromosome 22, and that rarely a deletion is inherited from a heterozygous or mosaic parent. ClinVar data in the packet list 23 pathogenic variants of the copy number loss and deletion types. On penetrance, GeneReviews states that small deletions involving SHANK3 may be associated with reduced penetrance and variable expressivity, that SHANK3 pathogenic variants have been associated with apparently non-syndromic autism and schizophrenia, and that classic manifestations have been seen with as little as 8 percent mosaicism in peripheral blood, based on unpublished data.

GeneReviews states that no clinical diagnostic criteria have been established and that diagnosis rests on laboratory testing that identifies a deletion of 22q13 including part or all of SHANK3, or a pathogenic variant in SHANK3. Its suggestive findings are moderate-to-profound developmental delay or intellectual disability with absent to severely delayed speech, together with features such as minor dysmorphic facial features, generalized hypotonia, decreased perspiration, mouthing of non-food items, decreased perception of pain, autism spectrum features, regression, epilepsy, and sleep disturbances. The diagnosis is established by a 50-kb to 9-Mb heterozygous deletion at 22q13.3 involving at least part of SHANK3, a heterozygous pathogenic or likely pathogenic variant in SHANK3, or a chromosomal rearrangement with breakpoints disrupting SHANK3; a variant of uncertain significance neither establishes nor rules out the diagnosis. GeneReviews states that chromosomal microarray analysis is often the first genetic test because most cases are caused by large copy number variants that sequence analysis cannot detect, and that detection of a terminal deletion is followed by screening for ring chromosome 22. The differential diagnosis includes deletions of 22q13 not involving SHANK3, 22q11.2 deletion syndrome, Prader-Willi syndrome, Angelman syndrome, and fragile X syndrome, among others.

The packet contains no approved_treatments records, so FDA-approved treatment coverage is not certified here. GeneReviews states that there is no cure and describes supportive care aimed at improving quality of life, maximizing function, and reducing complications through multidisciplinary specialist care. Its treatment table describes anti-seizure medications for epilepsy, noting that none have been demonstrated effective specifically for this disorder; immunomodulation therapy as a consideration for autoimmune encephalitis; sleep hygiene approaches; hearing aids and tympanostomy tubes; ophthalmology care and low vision services; feeding therapy, with gastrostomy tube placement possibly required for persistent feeding issues; standard specialist treatment of reflux, renal, thyroid, and pubertal concerns; dental care; compression approaches for lymphedema; and standard management of cardiac issues. Under therapies under investigation, GeneReviews describes lithium used for behavioral issues in three affected individuals and insulin-like growth factor-1, which showed improvement in social impairment and restrictive behavior in a placebo-controlled crossover study of nine children. The packet lists four orphan drug records, including an IGF-1 product and a SHANK3 gene therapy construct, all with DESIGNATED status, which is a designation and not an approval.

No natural history or explicit prognosis source is certified in this packet, so life expectancy and typical course are not stated. The GeneReviews clinical description reports that the severity of developmental delay tends to vary with deletion size, that individuals with the same deletion size can be vastly different in degree of disability, and that individuals with smaller deletions or SHANK3 variants not involving adjacent genes generally have better speech and language development.

ClinicalTrials.gov records in the packet include two Phase 3 studies of NNZ-2591 in pediatric participants sponsored by Neuren Pharmaceuticals Limited (NCT07281079 and the open-label NCT07593391, both recruiting) and two Phase 1 gene therapy studies: JAG201 in children and adults with SHANK3 haploinsufficiency (NCT06662188, Jaguar Gene Therapy, recruiting) and RB001 in children with SHANK3-related Phelan-McDermid syndrome (NCT07014020, Peking University First Hospital, active not recruiting). A web intervention for parents, WINGS (NCT06139172, Rush University Medical Center), is listed as active not recruiting. The packet identifies the Phelan-McDermid Syndrome Foundation, which has a registry, and CureSHANK as patient organizations.