Syndromic autism

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]

## Contents

* 1 Syndromic autism
* 2 Non-syndromic autism
* 3 Classification
* 3.1 Clinically defined
* 3.2 Molecularly defined
* 3.3 Currently undefined
* 4 References

## 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.[4][5] In most[quantify] 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.

## 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.

## Classification

A 2017 study[relevant? - discuss] 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 three genetic categories:[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, 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.[clarification needed]

Characteristics of syndromic ASD conditions  Condition | Cause | Chromosome(s) involved (if a mutation) | ASD prevalence (95% CI) | Clinically/Molecularly defined | Other characteristics | Ref.

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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 | [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, epilepsy, 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]
William's 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]

## References

1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 Benger, Matthew; Kinali, Maria; Mazarakis, Nicholas D. (December 2018). "Autism spectrum disorder: prospects for treatment using gene therapy". Molecular Autism 9 (1): 39. doi:10.1186/s13229-018-0222-8. PMID 29951185. PMC 6011246. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6011246/. Retrieved 26 May 2023.
2. ↑ 2.0 2.1 Sztainberg, Yehezkel; Zoghbi, Huda Y (November 2016). "Lessons learned from studying syndromic autism spectrum disorders". Nature Neuroscience 19 (11): 1408–1417. doi:10.1038/nn.4420. PMID 27786181. https://www.nature.com/articles/nn.4420. Retrieved 4 June 2023.
3. ↑ 3.00 3.01 3.02 3.03 3.04 3.05 3.06 3.07 3.08 3.09 3.10 3.11 Richards, Caroline; Jones, Christopher; Groves, Laura; Moss, Jo; Oliver, Chris (October 2015). "Prevalence of autism spectrum disorder phenomenology in genetic disorders: a systematic review and meta-analysis". The Lancet Psychiatry 2 (10): 909–916. doi:10.1016/S2215-0366(15)00376-4. PMID 26341300. https://www.thelancet.com/journals/lanpsy/article/PIIS2215-0366(15)00376-4/fulltext. Retrieved 27 May 2023.
4. ↑ 4.00 4.01 4.02 4.03 4.04 4.05 4.06 4.07 4.08 4.09 4.10 4.11 4.12 4.13 4.14 4.15 4.16 4.17 4.18 Fernandez, Bridget A.; Scherer, Stephen W. (31 December 2017). "Syndromic autism spectrum disorders: moving from a clinically defined to a molecularly defined approach". Dialogues in Clinical Neuroscience 19 (4): 353–371. doi:10.31887/DCNS.2017.19.4/sscherer. PMID 29398931. PMC 5789213. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5789213/. Retrieved 4 June 2023.
5. ↑ Bourgeron, Thomas (September 2015). "From the genetic architecture to synaptic plasticity in autism spectrum disorder". Nature Reviews Neuroscience 16 (9): 551–563. doi:10.1038/nrn3992. PMID 26289574. https://www.nature.com/articles/nrn3992. Retrieved 8 June 2023.
6. ↑ Marlborough, M.; Welham, A.; Jones, C.; Reckless, S.; Moss, J. (December 2021). "Autism spectrum disorder in females with fragile X syndrome: a systematic review and meta-analysis of prevalence". Journal of Neurodevelopmental Disorders 13 (1): 28. doi:10.1186/s11689-021-09362-5. PMID 34294028. PMC 8299695. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8299695/. Retrieved 30 May 2023.
7. ↑ Ramocki, Melissa B.; Peters, Sarika U.; Tavyev, Y. Jane; Zhang, Feng; Carvalho, Claudia M. B.; Schaaf, Christian P.; Richman, Ronald; Fang, Ping et al. (December 2009). "Autism and other neuropsychiatric symptoms are prevalent in individuals with MeCP2 duplication syndrome". Annals of Neurology 66 (6): 771–782. doi:10.1002/ana.21715. PMID 20035514. PMC 2801873. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2801873/. Retrieved 29 May 2023.
8. ↑ Soorya, Latha; Kolevzon, Alexander; Zweifach, Jessica; Lim, Teresa; Dobry, Yuriy; Schwartz, Lily; Frank, Yitzchak; Wang, A Ting et al. (December 2013). "Prospective investigation of autism and genotype-phenotype correlations in 22q13 deletion syndrome and SHANK3 deficiency". Molecular Autism 4 (1): 16. doi:10.1186/2040-2392-4-18. PMID 23758760. PMC 3707861. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3707861/. Retrieved 29 May 2023.
9. ↑ Splawski, Igor; Timothy, Katherine W.; Sharpe, Leah M.; Decher, Niels; Kumar, Pradeep; Bloise, Raffaella; Napolitano, Carlo; Schwartz, Peter J. et al. (October 2004). "CaV1.2 Calcium Channel Dysfunction Causes a Multisystem Disorder Including Arrhythmia and Autism". Cell 119 (1): 19–31. doi:10.1016/j.cell.2004.09.011. PMID 15454078. https://linkinghub.elsevier.com/retrieve/pii/S0092867404008426. Retrieved 29 May 2023.
10. ↑ Thurm, Audrey; Tierney, Elaine; Farmer, Cristan; Albert, Phebe; Joseph, Lisa; Swedo, Susan; Bianconi, Simona; Bukelis, Irena et al. (December 2016). "Development, behavior, and biomarker characterization of Smith-Lemli-Opitz syndrome: an update". Journal of Neurodevelopmental Disorders 8 (1): 12. doi:10.1186/s11689-016-9145-x. PMID 27053961. PMC 4822234. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4822234/. Retrieved 31 May 2023.
11. ↑ Cummings, Katherine; Watkins, Alice; Jones, Chris; Dias, Renuka; Welham, Alice (December 2022). "Behavioural and psychological features of PTEN mutations: a systematic review of the literature and meta-analysis of the prevalence of autism spectrum disorder characteristics". Journal of Neurodevelopmental Disorders 14 (1): 1. doi:10.1186/s11689-021-09406-w. PMID 34983360. PMC 8903687. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8903687/. Retrieved 27 May 2023.
12. ↑ Thomas, Andrea T.; Waite, Jane; Williams, Caitlin A.; Kirk, Jeremy; Oliver, Chris; Richards, Caroline (December 2022). "Phenotypic characteristics and variability in CHARGE syndrome: a PRISMA compliant systematic review and meta-analysis". Journal of Neurodevelopmental Disorders 14 (1): 49. doi:10.1186/s11689-022-09459-5. PMID 36045324. PMC 9429597. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9429597/. Retrieved 31 May 2023.
13. ↑ Norina, Usman; Moushumi, Sur (2023-03-06). "CHARGE Syndrome". StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK559199/.
14. ↑ Colleen A, Morris (2023-04-13). "Williams Syndrome". GeneReviews. https://www.ncbi.nlm.nih.gov/books/NBK1249/.
15. ↑ Bromley, Rebecca; Weston, Jennifer; Adab, Naghme; Greenhalgh, Janette; Sanniti, Anna; McKay, Andrew J; Tudur Smith, Catrin; Marson, Anthony G (30 October 2014). "Treatment for epilepsy in pregnancy: neurodevelopmental outcomes in the child". Cochrane Database of Systematic Reviews 2020 (6). doi:10.1002/14651858.CD010236.pub2. PMID 25354543. PMC 7390020. https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD010236.pub2/full. Retrieved 29 May 2023.
16. ↑ Clayton-Smith, Jill; Bromley, Rebecca; Dean, John; Journel, Hubert; Odent, Sylvie; Wood, Amanda; Williams, Janet; Cuthbert, Verna et al. (December 2019). "Diagnosis and management of individuals with Fetal Valproate Spectrum Disorder; a consensus statement from the European Reference Network for Congenital Malformations and Intellectual Disability". Orphanet Journal of Rare Diseases 14 (1): 180. doi:10.1186/s13023-019-1064-y. PMID 31324220. PMC 6642533. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6642533/. Retrieved 27 May 2023.

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