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.

Molecularly defined

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

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 disorder61.0% (46.0–74.0) [female individuals only] Clinically defined
Monogenic disorder100% [in a single study composed by 9 male participants] Clinically defined Brachycephaly, spasticity, recurrent respiratory infections, gastrointestinal hypermotility, genitourinary abnormalities, epilepsy, ID [7]
Monogenic disorder36.0% (33.0–40.0) Clinically defined Benign tumours in multiple organs, epilepsy
Monogenic disorder34.0% (24.0–37.0) Cheerful demeanour, microcephaly, epilepsy, speech deficits, sleep disturbance, epilepsy, ID
Monogenic disorder84% [in a single study composed by 32 participants] Molecularly defined [8]
Monogenic disorder80% [in a single study composed by 17 participants] Clinically defined [9]
Monogenic disorder55% [in a single study composed by 33 participants] [10]
Monogenic disorder18% (9.0–29.0) Clinically defined
Monogenic disorder17% (8–27) Clinically defined [11]
Chromosomal disorder16% (8.0–24.0) Clinically defined
Monogenic disorder54% (44.0–64.0) Clinically defined
Polygenic disorder 43% (32.0–53.0) Clinically defined
Monogenic disorder28% (16–41) Clinically defined [12] [13]
Polygenic disorder 15% (7.0–26.0)
Microdeletion syndrome12% (6.0–20.0) [14]
Microdeletion syndrome11% (5.0–19.0) Clinically defined
Teratogen8–15% [in VPA exposed children] Clinically defined [15] [16]

See also

Notes and References

  1. Benger . Matthew . Kinali . Maria . Mazarakis . Nicholas D. . Autism spectrum disorder: prospects for treatment using gene therapy . . December 2018 . 9 . 1 . 39 . 10.1186/s13229-018-0222-8 . 29951185 . 6011246 . free .
  2. 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.
  3. 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.
  4. 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.
  5. 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.
  6. 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 .
  7. 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.
  8. 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 .
  9. Splawski . Igor . Timothy . Katherine W. . Sharpe . Leah M. . Decher . Niels . Kumar . Pradeep . Bloise . Raffaella . Napolitano . Carlo . Schwartz . Peter J. . Joseph . Robert M. . Condouris . Karen . Tager-Flusberg . Helen . Priori . Silvia G. . Sanguinetti . Michael C. . Keating . Mark T. . CaV1.2 Calcium Channel Dysfunction Causes a Multisystem Disorder Including Arrhythmia and Autism . . October 2004 . 119 . 1 . 19–31 . 10.1016/j.cell.2004.09.011 . 15454078 . 15325633 . free .
  10. Thurm . Audrey . Tierney . Elaine . Farmer . Cristan . Albert . Phebe . Joseph . Lisa . Swedo . Susan . Bianconi . Simona . Bukelis . Irena . Wheeler . Courtney . Sarphare . Geeta . Lanham . Diane . Wassif . Christopher A. . Porter . Forbes D. . Development, behavior, and biomarker characterization of Smith-Lemli-Opitz syndrome: an update . . December 2016 . 8 . 1 . 12 . 10.1186/s11689-016-9145-x . 27053961 . 4822234 . free .
  11. 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 .
  12. 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 .
  13. 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.
  14. 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.
  15. Bromley . Rebecca . Weston . Jennifer . Adab . Naghme . Greenhalgh . Janette . Sanniti . Anna . McKay . Andrew J . Tudur Smith . Catrin . Marson . Anthony G . Treatment for epilepsy in pregnancy: neurodevelopmental outcomes in the child . . 30 October 2014 . 2020 . 6 . CD010236 . 10.1002/14651858.CD010236.pub2 . 25354543 . 7390020.
  16. Clayton-Smith . Jill . Bromley . Rebecca . Dean . John . Journel . Hubert . Odent . Sylvie . Wood . Amanda . Williams . Janet . Cuthbert . Verna . Hackett . Latha . Aslam . Neelo . Malm . Heli . James . Gregory . Westbom . Lena . Day . Ruth . Ladusans . Edmund . Jackson . Adam . Bruce . Iain . Walker . Robert . Sidhu . Sangeet . Dyer . Catrina . Ashworth . Jane . Hindley . Daniel . Diaz . Gemma Arca . Rawson . Myfanwy . Turnpenny . Peter . Diagnosis and management of individuals with Fetal Valproate Spectrum Disorder; a consensus statement from the European Reference Network for Congenital Malformations and Intellectual Disability . . December 2019 . 14 . 1 . 180 . 10.1186/s13023-019-1064-y . 31324220 . 6642533 . free .