Syndromic autism


Syndromic autism 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.
Studying the differences and similarities 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. SCN2A is the leading monogenic cause of autism.

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, typically confirmed by a targeted genetic testing.
  • Chromosomal
  • Syndromes caused by mutations in single genes
  • Syndromes caused by CNVs
  • Teratogens

Molecularly defined

Syndromes recognized by genome-wide testing, not by hypothesis-driven testing.
  • Chromosomal
  • Autism-associated genes
  • Autism-associated CNVs
ConditionCauseChromosome(s) involved ASD prevalence Clinically/Molecularly definedOther characteristics
Fragile X syndromeMonogenic disorder:
FMR1 		X 30%
 22%
14% 		Clinically defined Long/narrow face, macroorchidism, long ears and philtrum, hyperactivity, mild to moderate intellectual disability (ID), seizures
Rett syndromeMonogenic disorder:
MECP2		X61.0% Clinically definedMicrocephaly, breathing irregularities, language deficits, repetitive/stereotyped hand movements, epilepsy, ID
MECP2 duplication syndromeMonogenic disorder:
MECP2		X100% Clinically definedBrachycephaly, spasticity, recurrent respiratory infections, gastrointestinal hypermotility, genitourinary abnormalities, epilepsy, ID
Tuberous sclerosis complexMonogenic disorder:
TSC1
TSC2		9
16		 36.0% Clinically definedBenign tumours in multiple organs, epilepsy
Angelman's syndromeMonogenic disorder:
UBE3A		15 34.0% Cheerful demeanour, microcephaly, speech deficits, sleep disturbance, epilepsy, ID
Phelan-McDermid syndromeMonogenic disorder:
SHANK3		22 84% Molecularly defined
KCNH1-related disordersMonogenic disorder: KCNH11Molecularly defined, formerly clinically defined as Temple–Baraitser Syndrome or Zimmermann–Laband SyndromeMild to severe developmental delay, profound intellectual disability, neonatal hypotonia, myopathic facial appearance, and infantile-onset seizures
Timothy syndromeMonogenic disorder:
CACNA1C		12 80% Clinically defined
Smith-Lemli-Opitz syndromeMonogenic disorder:
DHCR7		1155%
Neurofibromatosis type IMonogenic disorder:
NF1		17 18% Clinically defined
PTEN hamartoma tumor syndromeMonogenic disorder:
PTEN		10 17% Clinically defined
Down syndromeChromosomal disorder:
trisomy 21		2116% Clinically defined
Cohen's syndromeMonogenic disorder:
VPS13B		8 54% Clinically defined
Cornelia de Lange syndromePolygenic disorder 43% Clinically defined
CHARGE syndromeMonogenic disorder:
CHD7		8 28% Clinically defined
Noonan's syndromePolygenic disorder 15%
Williams syndromeMicrodeletion syndrome:
7q11.23		7 12%
22q11.2 deletion syndromeMicrodeletion syndrome:
22q11.2		2211% Clinically defined
Fetal valproate spectrum disorderTeratogen:
valproate		 8–15% Clinically defined