# Syndromic autism

Syndromic autism (or syndromic autism spectrum disorder) denotes cases of autism spectrum disorder that are associated with a broader medical condition, generally a syndrome. Cases without such association, which account for the majority of total autism cases, are known as non-syndromic autism (or non-syndromic autism spectrum disorder).
Studying the differences and similarities (e.g., common pathways) between syndromic and non-syndromic cases can provide insights about the pathophysiology of autism and pave the way to new autism therapies.
Syndromic autism represents about 25% of the total ASD cases. In most cases, its etiology is known. Monogenic disorders are one of the causes of syndromic autism, which in this case are also known as monogenic autism spectrum disorders. They account for about 5% of the total ASD cases.

## Classification

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.
Following the proposal, ASD would be divided into genetic categories, including:

### Clinically defined

Syndromes recognized by clinicians (depending on their experience), typically confirmed by a targeted genetic testing.
* Chromosomal (e.g.: Down syndrome)
* Syndromes caused by mutations in single genes (e.g.: NF1, TSC, PTEN-associated macrocephaly syndrome, some males with FXS)
* Syndromes caused by CNVs (e.g.: microdeletion 22q11.2 syndrome)
* Teratogens (e.g., valproate aembryopathy)

### Molecularly defined

Syndromes recognized by genome-wide testing, not by hypothesis-driven testing (since clinical recognition is difficult).
* Chromosomal (e.g.: isodicentric 15q)
* ASD-risk genes (e.g.: ADNP, ARIDB1B, ANK2, SCN2A)
* ASD-associated CNVs (e.g.: 16p11.2 deletion/duplication, exonic NRXN1 deletions)
Characteristics of syndromic ASD conditions :
| Condition | Cause | Chromosome(s) involved (if a mutation) | ASD prevalence (95% CI) | Clinically/Molecularly defined | Other characteristics |
| 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 and philtrum, hyperactivity, mild to moderate intellectual disability (ID), seizures |
| 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 |
| 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 |
| Tuberous sclerosis complex | Monogenic disorder: TSC1 TSC2 | 9 16 | 36.0% (33.0–40.0) | Clinically defined | Benign tumours in multiple organs, epilepsy |
| Angelman's syndrome | Monogenic disorder: UBE3A | 15 | 34.0% (24.0–37.0) | | Cheerful demeanour, microcephaly, epilepsy, speech deficits, sleep disturbance, epilepsy, ID |
| Phelan-McDermid syndrome | Monogenic disorder: SHANK3 | 22 | 84% [in a single study composed by 32 participants] | Molecularly defined | |
| Timothy syndrome | Monogenic disorder: CACNA1C | 12 | 80% [in a single study composed by 17 participants] | Clinically defined | |
| Smith-Lemli-Opitz syndrome | Monogenic disorder: DHCR7 | 11 | 55% [in a single study composed by 33 participants] | | |
| Neurofibromatosis type I | Monogenic disorder: NF1 | 17 | 18% (9.0–29.0) | Clinically defined | |
| PTEN hamartoma tumor syndrome | Monogenic disorder: PTEN | 10 | 17% (8–27) | Clinically defined | |
| Down syndrome | Chromosomal disorder: trisomy 21 | 21 | 16% (8.0–24.0) | Clinically defined | |
| Cohen's syndrome | Monogenic disorder: VPS13B | 8 | 54% (44.0–64.0) | Clinically defined | |
| Cornelia de Lange syndrome | Polygenic disorder | | 43% (32.0–53.0) | Clinically defined | |
| CHARGE syndrome | Monogenic disorder: CHD7 | 8 | 28% (16–41) | Clinically defined | |
| Noonan's syndrome | Polygenic disorder | | 15% (7.0–26.0) | | |
| Williams syndrome | Microdeletion syndrome: 7q11.23 | 7 | 12% (6.0–20.0) | | |
| 22q11.2 deletion syndrome | Microdeletion syndrome: 22q11.2 | 22 | 11% (5.0–19.0) | Clinically defined | |
| Fetal valproate spectrum disorder | Teratogen: valproate | | 8–15% [in VPA exposed children] | Clinically defined | |