Syndromic autism

{{Short description|Autism associated with another medical condition}}

Syndromic autism (or syndromic autism spectrum disorder) 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 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.{{cite journal |last1=Benger |first1=Matthew |last2=Kinali |first2=Maria |last3=Mazarakis |first3=Nicholas D. |title=Autism spectrum disorder: prospects for treatment using gene therapy |journal=Molecular Autism |date=December 2018 |volume=9 |issue=1 |pages=39 |doi=10.1186/s13229-018-0222-8 |pmid=29951185 |pmc=6011246 |doi-access=free }}{{cite journal |last1=Sztainberg |first1=Yehezkel |last2=Zoghbi |first2=Huda Y |title=Lessons learned from studying syndromic autism spectrum disorders |journal=Nature Neuroscience |date=November 2016 |volume=19 |issue=11 |pages=1408–1417 |doi=10.1038/nn.4420 |pmid=27786181 |s2cid=3332899 |url=https://www.nature.com/articles/nn.4420 |access-date=4 June 2023|url-access=subscription }}{{cite journal |last1=Richards |first1=Caroline |last2=Jones |first2=Christopher |last3=Groves |first3=Laura |last4=Moss |first4=Jo |last5=Oliver |first5=Chris |title=Prevalence of autism spectrum disorder phenomenology in genetic disorders: a systematic review and meta-analysis |journal=The Lancet Psychiatry |date=October 2015 |volume=2 |issue=10 |pages=909–916 |doi=10.1016/S2215-0366(15)00376-4 |pmid=26341300 |url=https://www.thelancet.com/journals/lanpsy/article/PIIS2215-0366(15)00376-4/fulltext |access-date=27 May 2023}}{{cite journal |last1=Fernandez |first1=Bridget A. |last2=Scherer |first2=Stephen W. |title=Syndromic autism spectrum disorders: moving from a clinically defined to a molecularly defined approach |journal=Dialogues in Clinical Neuroscience |date=31 December 2017 |volume=19 |issue=4 |pages=353–371 |doi=10.31887/DCNS.2017.19.4/sscherer |pmid=29398931 |pmc=5789213}}

Syndromic autism represents about 25% of the total ASD cases.{{cite journal |last1=Bourgeron |first1=Thomas |title=From the genetic architecture to synaptic plasticity in autism spectrum disorder |journal=Nature Reviews Neuroscience |date=September 2015 |volume=16 |issue=9 |pages=551–563 |doi=10.1038/nrn3992 |pmid=26289574 |s2cid=12742356 |url=https://www.nature.com/articles/nrn3992 |access-date=8 June 2023|url-access=subscription }} 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.{{Citation needed|date=March 2025}}

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.{{Clarification needed|date=June 2023}}

Following the proposal, ASD would be divided into genetic categories, including:

= 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)
ASD-risk genes (e.g., ADNP, ARIDB1B, ANK2, SCN2A)
ASD-associated CNVs (e.g., 16p11.2 deletion/duplication, exonic NRXN1 deletions)

Condition	Cause	Chromosome(s) involved (if a mutation)	ASD prevalence (95% CI)	Clinically/Molecularly defined \|\| Other characteristics	{{refh}}
class="wikitable sortable" \|+ Characteristics of syndromic ASD conditions
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	{{cite journal \|last1=Marlborough \|first1=M. \|last2=Welham \|first2=A. \|last3=Jones \|first3=C. \|last4=Reckless \|first4=S. \|last5=Moss \|first5=J. \|title=Autism spectrum disorder in females with fragile X syndrome: a systematic review and meta-analysis of prevalence \|journal=Journal of Neurodevelopmental Disorders \|date=December 2021 \|volume=13 \|issue=1 \|pages=28 \|doi=10.1186/s11689-021-09362-5 \|pmid=34294028 \|pmc=8299695 \|doi-access=free }}
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
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	{{cite journal \|last1=Ramocki \|first1=Melissa B. \|last2=Peters \|first2=Sarika U. \|last3=Tavyev \|first3=Y. Jane \|last4=Zhang \|first4=Feng \|last5=Carvalho \|first5=Claudia M. B. \|last6=Schaaf \|first6=Christian P. \|last7=Richman \|first7=Ronald \|last8=Fang \|first8=Ping \|last9=Glaze \|first9=Daniel G. \|last10=Lupski \|first10=James R. \|last11=Zoghbi \|first11=Huda Y. \|title=Autism and other neuropsychiatric symptoms are prevalent in individuals with MeCP2 duplication syndrome \|journal=Annals of Neurology \|date=December 2009 \|volume=66 \|issue=6 \|pages=771–782 \|doi=10.1002/ana.21715 \|pmid=20035514 \|pmc=2801873}}
Tuberous sclerosis complex	Monogenic disorder: TSC1 TSC2	9 16	36.0% (33.0–40.0)	Clinically defined	Benign tumours in multiple organs, epilepsy
Angelman's syndrome	Monogenic disorder: UBE3A	15	34.0% (24.0–37.0)		Cheerful demeanour, microcephaly, speech deficits, sleep disturbance, epilepsy, ID
Phelan-McDermid syndrome	Monogenic disorder: SHANK3	22	84% [in a single study composed by 32 participants]	Molecularly defined		{{cite journal \|last1=Soorya \|first1=Latha \|last2=Kolevzon \|first2=Alexander \|last3=Zweifach \|first3=Jessica \|last4=Lim \|first4=Teresa \|last5=Dobry \|first5=Yuriy \|last6=Schwartz \|first6=Lily \|last7=Frank \|first7=Yitzchak \|last8=Wang \|first8=A Ting \|last9=Cai \|first9=Guiqing \|last10=Parkhomenko \|first10=Elena \|last11=Halpern \|first11=Danielle \|last12=Grodberg \|first12=David \|last13=Angarita \|first13=Benjamin \|last14=Willner \|first14=Judith P \|last15=Yang \|first15=Amy \|last16=Canitano \|first16=Roberto \|last17=Chaplin \|first17=William \|last18=Betancur \|first18=Catalina \|last19=Buxbaum \|first19=Joseph D \|title=Prospective investigation of autism and genotype-phenotype correlations in 22q13 deletion syndrome and SHANK3 deficiency \|journal=Molecular Autism \|date=December 2013 \|volume=4 \|issue=1 \|pages=16 \|doi=10.1186/2040-2392-4-18 \|pmid=23758760 \|pmc=3707861 \|doi-access=free }}
Timothy syndrome	Monogenic disorder: CACNA1C	12	80% [in a single study composed by 17 participants]	Clinically defined		{{cite journal \|last1=Splawski \|first1=Igor \|last2=Timothy \|first2=Katherine W. \|last3=Sharpe \|first3=Leah M. \|last4=Decher \|first4=Niels \|last5=Kumar \|first5=Pradeep \|last6=Bloise \|first6=Raffaella \|last7=Napolitano \|first7=Carlo \|last8=Schwartz \|first8=Peter J. \|last9=Joseph \|first9=Robert M. \|last10=Condouris \|first10=Karen \|last11=Tager-Flusberg \|first11=Helen \|last12=Priori \|first12=Silvia G. \|last13=Sanguinetti \|first13=Michael C. \|last14=Keating \|first14=Mark T. \|title=CaV1.2 Calcium Channel Dysfunction Causes a Multisystem Disorder Including Arrhythmia and Autism \|journal=Cell \|date=October 2004 \|volume=119 \|issue=1 \|pages=19–31 \|doi=10.1016/j.cell.2004.09.011 \|pmid=15454078 \|s2cid=15325633 \|doi-access=free }}
Smith-Lemli-Opitz syndrome	Monogenic disorder: DHCR7	11	55% [in a single study composed by 33 participants]			{{cite journal \|last1=Thurm \|first1=Audrey \|last2=Tierney \|first2=Elaine \|last3=Farmer \|first3=Cristan \|last4=Albert \|first4=Phebe \|last5=Joseph \|first5=Lisa \|last6=Swedo \|first6=Susan \|last7=Bianconi \|first7=Simona \|last8=Bukelis \|first8=Irena \|last9=Wheeler \|first9=Courtney \|last10=Sarphare \|first10=Geeta \|last11=Lanham \|first11=Diane \|last12=Wassif \|first12=Christopher A. \|last13=Porter \|first13=Forbes D. \|title=Development, behavior, and biomarker characterization of Smith-Lemli-Opitz syndrome: an update \|journal=Journal of Neurodevelopmental Disorders \|date=December 2016 \|volume=8 \|issue=1 \|pages=12 \|doi=10.1186/s11689-016-9145-x \|pmid=27053961 \|pmc=4822234 \|doi-access=free }}
Neurofibromatosis type I	Monogenic disorder: NF1	17	18% (9.0–29.0)	Clinically defined
PTEN hamartoma tumor syndrome	Monogenic disorder: PTEN	10	17% (8–27)	Clinically defined		{{cite journal \|last1=Cummings \|first1=Katherine \|last2=Watkins \|first2=Alice \|last3=Jones \|first3=Chris \|last4=Dias \|first4=Renuka \|last5=Welham \|first5=Alice \|title=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=Journal of Neurodevelopmental Disorders \|date=December 2022 \|volume=14 \|issue=1 \|pages=1 \|doi=10.1186/s11689-021-09406-w \|pmid=34983360 \|pmc=8903687 \|doi-access=free }}
Down syndrome	Chromosomal disorder: trisomy 21	21	16% (8.0–24.0)	Clinically defined
Cohen's syndrome	Monogenic disorder: VPS13B	8	54% (44.0–64.0)	Clinically defined
Cornelia de Lange syndrome	Polygenic disorder		43% (32.0–53.0)	Clinically defined
CHARGE syndrome	Monogenic disorder: CHD7	8	28% (16–41)	Clinically defined		{{cite journal \|last1=Thomas \|first1=Andrea T. \|last2=Waite \|first2=Jane \|last3=Williams \|first3=Caitlin A. \|last4=Kirk \|first4=Jeremy \|last5=Oliver \|first5=Chris \|last6=Richards \|first6=Caroline \|title=Phenotypic characteristics and variability in CHARGE syndrome: a PRISMA compliant systematic review and meta-analysis \|journal=Journal of Neurodevelopmental Disorders \|date=December 2022 \|volume=14 \|issue=1 \|pages=49 \|doi=10.1186/s11689-022-09459-5 \|pmid=36045324 \|pmc=9429597 \|doi-access=free }}{{Cite journal \|url=https://www.ncbi.nlm.nih.gov/books/NBK559199/ \|title=CHARGE Syndrome \|date=2023-03-06 \|access-date=2023-06-07 \|website=ncbi.nlm.nih.gov \|last1=Norina \|first1=Usman \|archive-url=https://archive.today/20230606220901/https://www.ncbi.nlm.nih.gov/books/NBK559199/ \|archive-date=2023-06-06 \|url-status=live\|publisher=StatPearls Publishing \|last2=Moushumi \|first2=Sur \|pmid=32644625 \|id=Bookshelf ID: NBK559199}}
Noonan's syndrome	Polygenic disorder		15% (7.0–26.0)
Williams syndrome	Microdeletion syndrome: 7q11.23	7	12% (6.0–20.0)			{{Cite journal \|url=https://www.ncbi.nlm.nih.gov/books/NBK1249/ \|title=Williams Syndrome \|date=2023-04-13 \|access-date=2023-06-07 \|website=ncbi.nlm.nih.gov \|last=Colleen A \|first=Morris \|archive-url=https://archive.today/20230606222743/https://www.ncbi.nlm.nih.gov/books/NBK1249/ \|archive-date=2023-06-06 \|url-status=live \|publisher=GeneReviews \|orig-date=9 April 1999 \|pmid=20301427 \|id=Bookshelf ID: NBK1249}}
22q11.2 deletion syndrome	Microdeletion syndrome: 22q11.2	22	11% (5.0–19.0)	Clinically defined
Fetal valproate spectrum disorder	Teratogen: valproate		8–15% [in VPA exposed children]	Clinically defined		{{cite journal \|last1=Bromley \|first1=Rebecca \|last2=Weston \|first2=Jennifer \|last3=Adab \|first3=Naghme \|last4=Greenhalgh \|first4=Janette \|last5=Sanniti \|first5=Anna \|last6=McKay \|first6=Andrew J \|last7=Tudur Smith \|first7=Catrin \|last8=Marson \|first8=Anthony G \|title=Treatment for epilepsy in pregnancy: neurodevelopmental outcomes in the child \|journal=Cochrane Database of Systematic Reviews \|date=30 October 2014 \|volume=2020 \|issue=6 \|pages=CD010236 \|doi=10.1002/14651858.CD010236.pub2 \|pmid=25354543 \|pmc=7390020}}{{cite journal \|last1=Clayton-Smith \|first1=Jill \|last2=Bromley \|first2=Rebecca \|last3=Dean \|first3=John \|last4=Journel \|first4=Hubert \|last5=Odent \|first5=Sylvie \|last6=Wood \|first6=Amanda \|last7=Williams \|first7=Janet \|last8=Cuthbert \|first8=Verna \|last9=Hackett \|first9=Latha \|last10=Aslam \|first10=Neelo \|last11=Malm \|first11=Heli \|last12=James \|first12=Gregory \|last13=Westbom \|first13=Lena \|last14=Day \|first14=Ruth \|last15=Ladusans \|first15=Edmund \|last16=Jackson \|first16=Adam \|last17=Bruce \|first17=Iain \|last18=Walker \|first18=Robert \|last19=Sidhu \|first19=Sangeet \|last20=Dyer \|first20=Catrina \|last21=Ashworth \|first21=Jane \|last22=Hindley \|first22=Daniel \|last23=Diaz \|first23=Gemma Arca \|last24=Rawson \|first24=Myfanwy \|last25=Turnpenny \|first25=Peter \|title=Diagnosis and management of individuals with Fetal Valproate Spectrum Disorder; a consensus statement from the European Reference Network for Congenital Malformations and Intellectual Disability \|journal=Orphanet Journal of Rare Diseases \|date=December 2019 \|volume=14 \|issue=1 \|pages=180 \|doi=10.1186/s13023-019-1064-y \|pmid=31324220 \|pmc=6642533 \|doi-access=free }}

Syndromic autism

Classification

= Clinically defined =

= Molecularly defined =

See also

References