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Syndromic autism (orsyndromic autism spectrum disorder) denotes cases ofautism that are associated with a broadermedical condition, generally asyndrome. Cases without such association, which account for the majority of total autism cases, are known asnon-syndromic autism (ornon-syndromic autism spectrum disorder).
Studying the differences and similarities (e.g., commonpathways) between syndromic and non-syndromic cases can provide insights about thepathophysiology of autism and pave the way to newautism therapies.[1][2][3][4]
Syndromic autism represents about 25% of the total ASD cases.[4][5] In most cases, itsetiology is known.[2][4]Monogenic disorders are one of the causes of syndromic autism, which in this case are also known asmonogenic autism spectrum disorders. They account for about 5% of the total ASD cases.[citation needed]
A 2017 study proposed to replace the classification syndromic/non-syndromic ASD into one based on the genetic etiology of the condition, specifying if the syndromic condition occurs in the context of a "phenotype first" clinically defined syndrome or from a "genotype first" molecularly defined syndrome.[4][clarification needed]
Following the proposal, ASD would be divided into genetic categories, including:[4]
Syndromes recognized by clinicians (depending on their experience), typically confirmed by a targetedgenetic testing.
Syndromes recognized by genome-wide testing, not by hypothesis-driven testing (since clinical recognition is difficult).
| Condition | Cause | Chromosome(s) involved (if a mutation) | ASD prevalence (95% CI) | Clinically/Molecularly defined | Other characteristics | Ref. |
|---|---|---|---|---|---|---|
| Fragile X syndrome | Monogenic disorder: FMR1 (encodes FMRP) | X | 30% (20.0–31.0) [male individuals only] 22% (15.0–30.0) [mixed sex] 14% (13–18) [female individuals only] | Clinically defined [in some males] | Long/narrow face,macroorchidism, long ears andphiltrum,hyperactivity, mild to moderateintellectual disability (ID),seizures | [1][3][4][6] |
| Rett syndrome | Monogenic disorder: MECP2 | X | 61.0% (46.0–74.0) [female individuals only] | Clinically defined | Microcephaly, breathing irregularities, language deficits, repetitive/stereotyped hand movements,epilepsy,ID | [1][3][4] |
| MECP2 duplication syndrome | Monogenic disorder: MECP2 | X | 100% [in a single study composed by 9 male participants] | Clinically defined | Brachycephaly,spasticity, recurrent respiratory infections, gastrointestinal hypermotility,genitourinary abnormalities, epilepsy, ID | [1][4][7] |
| Tuberous sclerosis complex | Monogenic disorder: TSC1 TSC2 | 9 16 | 36.0% (33.0–40.0) | Clinically defined | Benign tumours in multiple organs, epilepsy | [1][3][4] |
| Angelman's syndrome | Monogenic disorder: UBE3A | 15 | 34.0% (24.0–37.0) | Cheerful demeanour,microcephaly, speech deficits, sleep disturbance,epilepsy, ID | [1][3] | |
| Phelan-McDermid syndrome | Monogenic disorder: SHANK3 | 22 | 84% [in a single study composed by 32 participants] | Molecularly defined | [4][8] | |
| KCNH1-related disorders | Monogenic disorder:KCNH1 | 1 | Molecularly defined, formerly clinically defined asTemple–Baraitser Syndrome orZimmermann–Laband Syndrome | Mild to severe developmental delay, profound intellectual disability, neonatal hypotonia, myopathic facial appearance, and infantile-onset seizures | [9] | |
| Timothy syndrome | Monogenic disorder: CACNA1C | 12 | 80% [in a single study composed by 17 participants] | Clinically defined | [4][10] | |
| Smith-Lemli-Opitz syndrome | Monogenic disorder: DHCR7 | 11 | 55% [in a single study composed by 33 participants] | [11] | ||
| Neurofibromatosis type I | Monogenic disorder: NF1 | 17 | 18% (9.0–29.0) | Clinically defined | [3][4] | |
| PTEN hamartoma tumor syndrome | Monogenic disorder: PTEN | 10 | 17% (8–27) | Clinically defined | [4][12] | |
| Down syndrome | Chromosomal disorder: trisomy21 | 21 | 16% (8.0–24.0) | Clinically defined | [3][4] | |
| Cohen's syndrome | Monogenic disorder: VPS13B | 8 | 54% (44.0–64.0) | Clinically defined | [3][4] | |
| Cornelia de Lange syndrome | Polygenic disorder | 43% (32.0–53.0) | Clinically defined | [3][4] | ||
| CHARGE syndrome | Monogenic disorder: CHD7 | 8 | 28% (16–41) | Clinically defined | [4][13][14] | |
| Noonan's syndrome | Polygenic disorder | 15% (7.0–26.0) | [3] | |||
| Williams syndrome | Microdeletion syndrome: 7q11.23 | 7 | 12% (6.0–20.0) | [3][15] | ||
| 22q11.2 deletion syndrome | Microdeletion syndrome: 22q11.2 | 22 | 11% (5.0–19.0) | Clinically defined | [3][4] | |
| Fetal valproate spectrum disorder | Teratogen: valproate | 8–15% [in VPA exposed children] | Clinically defined | [4][16][17] |
