Syndromic autism explained

Syndromic autism (or syndromic autism spectrum disorders) 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 disorders).

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

Autism spectrum disorder (ASD) is referred to as syndromic when it is one of the many characteristics associated with a broader medical condition, generally a syndrome.

Syndromic autism represents about 25% of the total ASD cases.^[5] 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.

Certain syndromic forms of ASD can also have different phenomenology.

Non-syndromic autism

Non-syndromic autism, also called classic autism or idiopathic autism (as in most cases, the etiology is unknown), represents the majority of total autism cases.

In most cases, its cause is polygenic.

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 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

Currently undefined.

Characteristics of syndromic ASD conditions
Condition	Cause	Chromosome(s) involved (if a mutation)	ASD prevalence (95% CI)	Clinically/Molecularly defined	Other characteristics !
	Monogenic disorder FMR1 (encodes FMRP)		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	^[6]
	Monogenic disorder		61.0% (46.0–74.0) [female individuals only]	Clinically defined
	Monogenic disorder		100% [in a single study composed by 9 male participants]	Clinically defined	Brachycephaly, spasticity, recurrent respiratory infections, gastrointestinal hypermotility, genitourinary abnormalities, epilepsy, ID	^[7]
	Monogenic disorder		36.0% (33.0–40.0)	Clinically defined	Benign tumours in multiple organs, epilepsy
	Monogenic disorder		34.0% (24.0–37.0)		Cheerful demeanour, microcephaly, epilepsy, speech deficits, sleep disturbance, epilepsy, ID
	Monogenic disorder		84% [in a single study composed by 32 participants]	Molecularly defined		^[8]
	Monogenic disorder		80% [in a single study composed by 17 participants]	Clinically defined		^[9]
	Monogenic disorder		55% [in a single study composed by 33 participants]			^[10]
	Monogenic disorder		18% (9.0–29.0)	Clinically defined
	Monogenic disorder		17% (8–27)	Clinically defined		^[11]
	Chromosomal disorder		16% (8.0–24.0)	Clinically defined
	Monogenic disorder		54% (44.0–64.0)	Clinically defined
	Polygenic disorder		43% (32.0–53.0)	Clinically defined
	Monogenic disorder		28% (16–41)	Clinically defined		^[12] ^[13]
	Polygenic disorder		15% (7.0–26.0)
	Microdeletion syndrome		12% (6.0–20.0)			^[14]
	Microdeletion syndrome		11% (5.0–19.0)	Clinically defined
	Teratogen		8–15% [in VPA exposed children]	Clinically defined		^[15] ^[16]

Notes and References

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Sztainberg . Yehezkel . Zoghbi . Huda Y . Lessons learned from studying syndromic autism spectrum disorders . . November 2016 . 19 . 11 . 1408–1417 . 10.1038/nn.4420 . 27786181 . 3332899 . 4 June 2023.
Richards . Caroline . Jones . Christopher . Groves . Laura . Moss . Jo . Oliver . Chris . Prevalence of autism spectrum disorder phenomenology in genetic disorders: a systematic review and meta-analysis . . October 2015 . 2 . 10 . 909–916 . 10.1016/S2215-0366(15)00376-4 . 26341300 . 27 May 2023.
Fernandez . Bridget A. . Scherer . Stephen W. . Syndromic autism spectrum disorders: moving from a clinically defined to a molecularly defined approach . . 31 December 2017 . 19 . 4 . 353–371 . 10.31887/DCNS.2017.19.4/sscherer . 29398931 . 5789213.
Bourgeron . Thomas . From the genetic architecture to synaptic plasticity in autism spectrum disorder . . September 2015 . 16 . 9 . 551–563 . 10.1038/nrn3992 . 26289574 . 12742356 . 8 June 2023.
Marlborough . M. . Welham . A. . Jones . C. . Reckless . S. . Moss . J. . Autism spectrum disorder in females with fragile X syndrome: a systematic review and meta-analysis of prevalence . . December 2021 . 13 . 1 . 28 . 10.1186/s11689-021-09362-5 . 34294028 . 8299695 . free .
Ramocki . Melissa B. . Peters . Sarika U. . Tavyev . Y. Jane . Zhang . Feng . Carvalho . Claudia M. B. . Schaaf . Christian P. . Richman . Ronald . Fang . Ping . Glaze . Daniel G. . Lupski . James R. . Zoghbi . Huda Y. . Autism and other neuropsychiatric symptoms are prevalent in individuals with MeCP2 duplication syndrome . . December 2009 . 66 . 6 . 771–782 . 10.1002/ana.21715 . 20035514 . 2801873.
Soorya . Latha . Kolevzon . Alexander . Zweifach . Jessica . Lim . Teresa . Dobry . Yuriy . Schwartz . Lily . Frank . Yitzchak . Wang . A Ting . Cai . Guiqing . Parkhomenko . Elena . Halpern . Danielle . Grodberg . David . Angarita . Benjamin . Willner . Judith P . Yang . Amy . Canitano . Roberto . Chaplin . William . Betancur . Catalina . Buxbaum . Joseph D . Prospective investigation of autism and genotype-phenotype correlations in 22q13 deletion syndrome and SHANK3 deficiency . . December 2013 . 4 . 1 . 16 . 10.1186/2040-2392-4-18 . 23758760 . 3707861 . free .
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Cummings . Katherine . Watkins . Alice . Jones . Chris . Dias . Renuka . Welham . Alice . Behavioural and psychological features of PTEN mutations: a systematic review of the literature and meta-analysis of the prevalence of autism spectrum disorder characteristics . . December 2022 . 14 . 1 . 1 . 10.1186/s11689-021-09406-w . 34983360 . 8903687 . free .
Thomas . Andrea T. . Waite . Jane . Williams . Caitlin A. . Kirk . Jeremy . Oliver . Chris . Richards . Caroline . Phenotypic characteristics and variability in CHARGE syndrome: a PRISMA compliant systematic review and meta-analysis . . December 2022 . 14 . 1 . 49 . 10.1186/s11689-022-09459-5 . 36045324 . 9429597 . free .
CHARGE Syndrome . 2023-03-06 . 2023-06-07 . . Norina . Usman . https://archive.today/20230606220901/https://www.ncbi.nlm.nih.gov/books/NBK559199/ . 2023-06-06 . live. . Moushumi . Sur . 32644625 . Bookshelf ID: NBK559199.
Williams Syndrome . 2023-04-13 . 2023-06-07 . . Colleen A . Morris . https://archive.today/20230606222743/https://www.ncbi.nlm.nih.gov/books/NBK1249/ . 2023-06-06 . live . . 9 April 1999 . 20301427 . Bookshelf ID: NBK1249.
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