Syndromic autism

Main article: Autism spectrum

Autism spectrum disorder can be classified in two categories: "syndromic autism" and "non-syndromic autism". ASD is syndromic when it is one of the many characteristics that are associated with a more broad medical condition, generally a syndrome. Syndromic autism represents about 25% of the total ASD cases and its etiology in most cases is known. Monogenic disorders are one of the causes of syndromic autism (in this case also known as "monogenic ASD"), they account for about 5% of the total ASD cases. Non-syndromic autism, also called "classic autism" and "idiopathic autism" (because in most cases etiology is unknown), represents the majority of total autism cases and in most cases its cause is polygenic. Certain syndromic form of ASD can also have different phenomenology. Studying the differences and similarities (e.g. common pathways) between syndromic and non-syndromic autism can also give more insight about its pathophysiology and pave the way to new treatments.
A 2017 study, also proposed to replace the classification "syndromic"/"non-syndromic" ASD into a 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. In this case ASD would be divided into three genetic categories:

• "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)}
• "Currently undefined"

Characteristics of syndromic ASD conditions

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 and philtrum, mild to moderate intellectual disability, hyperactivity, 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)
William's 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