Syndromic autism

Syndromic autism (or syndromic autism spectrum disorder) denotes cases of autism 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.^[1][2][3][4]

Syndromic autism represents about 25% of the total ASD cases.^[4][5] In most cases, its etiology is known.^[2][4] 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.^{[citation needed]}

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.^{[4][clarification needed]}

Following the proposal, ASD would be divided into genetic categories, including:^[4]

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 mutation, tuberous sclerosis, PTEN-associated macrocephaly syndrome, some males with fragile X syndrome)
• Syndromes caused by CNVs (e.g., DiGeorge syndrome)
• Teratogens (e.g., fetal valproate spectrum disorder)

Molecularly defined

Syndromes recognized by genome-wide testing, not by hypothesis-driven testing (since clinical recognition is difficult).

• Chromosomal (e.g., isodicentric 15q)
• Autism-associated genes (e.g., ADNP, ARIDB1B, ANK2, SCN2A)
• Autism-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	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, hyperactivity, mild to moderate intellectual 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]
Timothy syndrome	Monogenic disorder: CACNA1C	12	80% [in a single study composed by 17 participants]	Clinically defined		[4][9]
Smith-Lemli-Opitz syndrome	Monogenic disorder: DHCR7	11	55% [in a single study composed by 33 participants]			[10]
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][11]
Down syndrome	Chromosomal disorder: trisomy 21	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][12][13]
Noonan's syndrome	Polygenic disorder		15% (7.0–26.0)			[3]
Williams syndrome	Microdeletion syndrome: 7q11.23	7	12% (6.0–20.0)			[3][14]
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][15][16]

See also

• Causes of autism
• Conditions comorbid to autism