Human Gene Module / Chromosome 15 / MAGEL2

MAGEL2MAGE-like 2

SFARI Gene Score
1S
High Confidence, Syndromic Criteria 1.1, Syndromic
Autism Reports / Total Reports
3 / 25
Rare Variants / Common Variants
50 / 0
Aliases
MAGEL2, NDNL1,  nM15
Associated Syndromes
Schaaf-Yang syndrome, Chitayat-Hall syndrome, Schaaf-Yang syndrome, DD
Chromosome Band
15q11.2
Associated Disorders
DD/NDD, ADHD, ID, EPS, ASD
Relevance to Autism

Truncating variants on the paternal allele of the MAGEL2 gene were identified in four individuals presenting with autism spectrum disorder (ASD), intellectual disability and a varying degree of clinical and behavioral features of Prader-Willi syndrome (PWS) (Schaaf et al., 2013).

Molecular Function

The protein encoded by this paternally-imprinted gene may enhance ubiquitin ligase activity of RING-type zinc finger-containing E3 ubiquitin-protein ligases and has been proposed to act through recruitment and/or stabilization of the Ubl-conjugating enzyme (E2) at the E3:substrate complex. This gene may play a role in Prader-Willi syndrome (PWS, OMIM 176270), a contiguous gene syndrome characterized by muscular hypotonia, mental retardation, short stature, obesity, hypogonadotropic hypogonadism, and small hands and feet that results from inactivity of the paternal copies of a number of genes on 15q11, through deletion or disruption of these genes or maternal uniparental disomy 15.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
Mouse
Entrez GeneMouse Genome Informatics
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to MAGEL2 (25 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Truncating mutations of MAGEL2 cause Prader-Willi phenotypes and autism Schaaf CP , et al. (2013) No ASD, ID
2 Support Effectiveness of exome and genome sequencing guided by acuity of illness for diagnosis of neurodevelopmental disorders Soden SE , et al. (2014) No DD, ASD
3 Recent Recommendation Truncating Mutations of MAGEL2, a Gene within the Prader-Willi Locus, Are Responsible for Severe Arthrogryposis Mejlachowicz D , et al. (2015) No -
4 Recent Recommendation The phenotypic spectrum of Schaaf-Yang syndrome: 18 new affected individuals from 14 families Fountain MD , et al. (2016) No DD, ID, ASD, epilepsy/seizures
5 Recent Recommendation Loss of Magel2 impairs the development of hypothalamic Anorexigenic circuits Maillard J , et al. (2016) No -
6 Support Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability Lelieveld SH et al. (2016) No -
7 Support Clinical exome sequencing: results from 2819 samples reflecting 1000 families Trujillano D , et al. (2016) No DD, microcephaly
8 Support A De Novo Nonsense Mutation in MAGEL2 in a Patient Initially Diagnosed as Opitz-C: Similarities Between Schaaf-Yang and Opitz-C Syndromes Urreizti R , et al. (2017) No Features of Opitz trigonocephaly C syndrome, ID
9 Support Genomic diagnosis for children with intellectual disability and/or developmental delay Bowling KM , et al. (2017) No -
10 Support Pitfalls of trio-based exome sequencing: imprinted genes and parental mosaicism-MAGEL2 as an example Palomares-Bralo M , et al. (2017) No DD
11 Support Three patients with Schaaf-Yang syndrome exhibiting arthrogryposis and endocrinological abnormalities Enya T , et al. (2018) No Autistic behavior
12 Support Chitayat-Hall and Schaaf-Yang syndromes:a common aetiology: expanding the phenotype of MAGEL2-related disorders Jobling R , et al. (2018) No ASD
13 Recent Recommendation Schaaf-Yang syndrome overview: Report of 78 individuals McCarthy J , et al. (2018) No ASD
14 Support A Novel Mutation of MAGEL2 in a Patient with Schaaf-Yang Syndrome and Hypopituitarism D Hidalgo-Santos A , et al. (2018) No ASD
15 Support Neurocognitive and Neurobehavioral Phenotype of Youth with Schaaf-Yang Syndrome Thomason MM , et al. (2018) No ASD
16 Support MAGEL2-related disorders: A study and case series Patak J , et al. (2019) No ASD, ADHD
17 Support The adult phenotype of Schaaf-Yang syndrome Marbach F et al. (2020) No ASD
18 Support - Ahn H et al. (2020) No ASD or autistic features, epilepsy/seizures
19 Support - Duan Y et al. (2021) No DD, ID, autistic features
20 Support - Bosque Ortiz GM et al. (2021) No -
21 Support - Woodbury-Smith M et al. (2022) Yes -
22 Support - Negishi Y et al. (2022) No ASD
23 Support - Yuan B et al. (2023) Yes -
24 Support - Sheth F et al. (2023) Yes DD, ID, epilepsy/seizures
25 Support - et al. () No -
Rare Variants   (50)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.1687C>T p.Gln563Ter stop_gained Unknown - - 34128869 Duan Y et al. (2021)
c.2874G>A p.Trp958Ter stop_gained De novo - - 33076953 Marbach F et al. (2020)
c.1354C>T p.Arg452Cys missense_variant De novo - - 36881370 Yuan B et al. (2023)
c.3124C>T p.Gln1042Ter stop_gained De novo - - 24076603 Schaaf CP , et al. (2013)
c.3208G>T p.Glu1070Ter stop_gained De novo - - 28554332 Bowling KM , et al. (2017)
c.1912C>T p.Gln638Ter stop_gained De novo - - 27195816 Fountain MD , et al. (2016)
c.2873G>A p.Trp958Ter stop_gained Unknown - - 27195816 Fountain MD , et al. (2016)
c.3131C>A p.Ser1044Ter stop_gained De novo - Simplex 29359444 Enya T , et al. (2018)
c.3169G>T p.Glu1057Ter stop_gained De novo - Simplex 31397880 Patak J , et al. (2019)
c.1819C>T p.Gln607Ter stop_gained Familial Paternal - 33076953 Marbach F et al. (2020)
c.1912C>T p.Gln638Ter stop_gained De novo - Simplex 28281571 Urreizti R , et al. (2017)
c.1996dup p.Gln666ProfsTer47 frameshift_variant De novo - - 33371171 Ahn H et al. (2020)
c.1762C>T p.Gln588Ter stop_gained Unknown - Multiplex 29599419 Jobling R , et al. (2018)
c.1996dupC p.Gln666fs frameshift_variant De novo - - 27195816 Fountain MD , et al. (2016)
c.3019C>T p.Gln1007Ter stop_gained De novo - - 30323850 D Hidalgo-Santos A , et al. (2018)
c.1621C>T p.Gln541Ter stop_gained Familial Paternal - 27195816 Fountain MD , et al. (2016)
c.1996dup p.Gln666ProfsTer47 frameshift_variant De novo - - 31397880 Patak J , et al. (2019)
c.2958del p.Ser987AlafsTer5 frameshift_variant De novo - - 33076953 Marbach F et al. (2020)
c.3235G>T p.Glu1079Ter stop_gained Familial Paternal - 27195816 Fountain MD , et al. (2016)
c.2821dup p.Arg941ProfsTer10 frameshift_variant Unknown - - 33076953 Marbach F et al. (2020)
c.1158_1161del p.Thr388GlyfsTer48 frameshift_variant Unknown - Multiplex 38438125 et al. ()
c.1790del p.Pro597HisfsTer105 frameshift_variant Unknown - - 33076953 Marbach F et al. (2020)
c.1800del p.Pro601GlnfsTer101 frameshift_variant De novo - - 33076953 Marbach F et al. (2020)
c.3288T>C p.His1096%3D synonymous_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.1912C>T p.Gln638Ter stop_gained Familial Paternal Multiplex 29359444 Enya T , et al. (2018)
c.2217del p.Lys740ArgfsTer11 frameshift_variant De novo - Simplex 33371171 Ahn H et al. (2020)
c.1996dup p.Gln666ProfsTer47 frameshift_variant De novo - - 27479843 Lelieveld SH et al. (2016)
c.1580del p.Pro527ArgfsTer175 frameshift_variant Unknown - - 27195816 Fountain MD , et al. (2016)
c.1996dupC p.Gln666ProfsTer47 frameshift_variant Familial Paternal - 33371171 Ahn H et al. (2020)
c.1613C>A p.Ala538Glu missense_variant Familial Paternal Simplex 31397880 Patak J , et al. (2019)
c.3122del p.Val1041AlafsTer7 frameshift_variant De novo - Simplex 31397880 Patak J , et al. (2019)
c.3181_3182del p.Ile1061HisfsTer7 frameshift_variant De novo - - 24076603 Schaaf CP , et al. (2013)
c.1930C>G p.Gln644Glu missense_variant Unknown - Extended multiplex 37543562 Sheth F et al. (2023)
c.2179_2180del p.Asp727ProfsTer6 frameshift_variant - - Multiplex 29599419 Jobling R , et al. (2018)
c.1652del p.Val551AspfsTer151 frameshift_variant De novo - Simplex 24076603 Schaaf CP , et al. (2013)
c.1801_1802del p.Pro601AsnfsTer111 frameshift_variant Unknown - - 27195816 Fountain MD , et al. (2016)
c.1996dupC p.Gln666ProfsTer47 frameshift_variant De novo - Multiplex 25473036 Soden SE , et al. (2014)
c.1996dup p.Gln666ProfsTer47 frameshift_variant De novo - Simplex 27848944 Trujillano D , et al. (2016)
- - complex_structural_alteration Familial Paternal Multi-generational 29599419 Jobling R , et al. (2018)
c.2118del p.Leu708TrpfsTer7 frameshift_variant De novo - Simplex 26365340 Mejlachowicz D , et al. (2015)
c.1802del p.Pro601GlnfsTer101 frameshift_variant Unknown Not maternal - 24076603 Schaaf CP , et al. (2013)
c.1996dupC p.Gln666fs frameshift_variant Familial Paternal Multiplex 27195816 Fountain MD , et al. (2016)
c.3449_3450del p.Phe1150TrpfsTer4 frameshift_variant Familial Paternal Simplex 33371171 Ahn H et al. (2020)
c.1996dup p.Gln666ProfsTer47 frameshift_variant Familial Paternal Simplex 29599419 Jobling R , et al. (2018)
c.1996_1997insCA p.Gln666ProfsTer37 frameshift_variant Familial Paternal Simplex 31397880 Patak J , et al. (2019)
c.1996dupC p.Gln666fs frameshift_variant Familial Paternal Extended multiplex 27195816 Fountain MD , et al. (2016)
c.1996del p.Gln666SerfsTer36 frameshift_variant Familial Paternal Multiplex 26365340 Mejlachowicz D , et al. (2015)
c.1996dup p.Gln666ProfsTer47 frameshift_variant Familial Paternal Simplex 28640240 Palomares-Bralo M , et al. (2017)
c.1996dup p.Gln666ProfsTer47 frameshift_variant Familial Paternal Extended multiplex 27195816 Fountain MD , et al. (2016)
c.2170_2171insTCTTCTATAGACCGCAGGGGCTCCTCTAAAGAGCGCAGGACCTCCTCGAAGGAGCGCAGGGCC p.Ser724delinsPhePheTyrArgProGlnGlyLeuLeuTer inframe_insertion Unknown - - 33076953 Marbach F et al. (2020)
Common Variants  

No common variants reported.

SFARI Gene score
1S

High Confidence, Syndromic

Score Delta: Score remained at 1S

criteria met
See SFARI Gene'scoring criteria
1

High Confidence

See all Category 1 Genes

We considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.

S

Syndromic

See all Category S Genes

The syndromic category includes mutations that are associated with a substantial degree of increased risk and consistently linked to additional characteristics not required for an ASD diagnosis. If there is independent evidence implicating a gene in idiopathic ASD, it will be listed as "#S" (e.g., 2S, 3S, etc.). If there is no such independent evidence, the gene will be listed simply as "S."

1/1/2021
1
icon
1

Score remained at 1

Description

A de novo frameshift variant on the paternal allele of the MAGEL2 gene was identified in a male patient with ASD, mild intellectual disability, and a history of Prader-Willi-like phenotypes; this variant was absent in dbSNP, 1000 Genomes, and ESP5000 . A search of the Baylor College of Medicine Whole-Genome Laboratory database identified an additional three subjects with loss-of-function variants on the paternal allele of MAGEL2 (two of which were de novo) who also presented with ASD, intellectual disability, and some or all of the clinical and behavioral features of Prader-Willi syndrome (PMID 24076603). A frameshift variant in MAGEL2 (c.1996dupC;p.Gln666ProfsTer47) was identified in two siblings presenting with Schaaf-Yang syndrome, one of whom was diagnosed with ASD; this variant was undetectable in DNA from the blood of either parent, suggesting gonadal mosaicism of this paternally expressed gene (Soden et al., 2014). Fountain et al., 2016 reported a total of 18 newly identified individuals with Schaaf-Yang syndrome from 14 families. Of the seven newly identified cases in Fountain et al., 2016 that were formally evaluated for ASD, four cases were formally diagnosed with ASD (including two paternal cousins with a paternally-inherited frameshift variant and a case with a de novo frameshift variant); an additional six cases presented with autistic behaviors but were not formally evaluated for ASD. McCarthy et al., 2018 reported the phenotypes of an international cohort of 78 patients with nonsense or frameshift mutations in MAGEL2 (43 previously reported individuals, 35 newly identified individuals) and found that, of the 32 individuals in this cohort that had been formally evaluated for ASD using ADOS-2 and ADI-R, 25 were formally diagnosed with ASD (78%).

Reports Added
[Diagnosis of Schaaf-Yang syndrome in Korean children with developmental delay and hypotonia2020]
10/1/2020
1
icon
1

Score remained at 1

Description

A de novo frameshift variant on the paternal allele of the MAGEL2 gene was identified in a male patient with ASD, mild intellectual disability, and a history of Prader-Willi-like phenotypes; this variant was absent in dbSNP, 1000 Genomes, and ESP5000 . A search of the Baylor College of Medicine Whole-Genome Laboratory database identified an additional three subjects with loss-of-function variants on the paternal allele of MAGEL2 (two of which were de novo) who also presented with ASD, intellectual disability, and some or all of the clinical and behavioral features of Prader-Willi syndrome (PMID 24076603). A frameshift variant in MAGEL2 (c.1996dupC;p.Gln666ProfsTer47) was identified in two siblings presenting with Schaaf-Yang syndrome, one of whom was diagnosed with ASD; this variant was undetectable in DNA from the blood of either parent, suggesting gonadal mosaicism of this paternally expressed gene (Soden et al., 2014). Fountain et al., 2016 reported a total of 18 newly identified individuals with Schaaf-Yang syndrome from 14 families. Of the seven newly identified cases in Fountain et al., 2016 that were formally evaluated for ASD, four cases were formally diagnosed with ASD (including two paternal cousins with a paternally-inherited frameshift variant and a case with a de novo frameshift variant); an additional six cases presented with autistic behaviors but were not formally evaluated for ASD. McCarthy et al., 2018 reported the phenotypes of an international cohort of 78 patients with nonsense or frameshift mutations in MAGEL2 (43 previously reported individuals, 35 newly identified individuals) and found that, of the 32 individuals in this cohort that had been formally evaluated for ASD using ADOS-2 and ADI-R, 25 were formally diagnosed with ASD (78%).

Reports Added
[The adult phenotype of Schaaf-Yang syndrome2020]
10/1/2019
2S
icon
1

Decreased from 2S to 1

New Scoring Scheme
Description

A de novo frameshift variant on the paternal allele of the MAGEL2 gene was identified in a male patient with ASD, mild intellectual disability, and a history of Prader-Willi-like phenotypes; this variant was absent in dbSNP, 1000 Genomes, and ESP5000 . A search of the Baylor College of Medicine Whole-Genome Laboratory database identified an additional three subjects with loss-of-function variants on the paternal allele of MAGEL2 (two of which were de novo) who also presented with ASD, intellectual disability, and some or all of the clinical and behavioral features of Prader-Willi syndrome (PMID 24076603). A frameshift variant in MAGEL2 (c.1996dupC;p.Gln666ProfsTer47) was identified in two siblings presenting with Schaaf-Yang syndrome, one of whom was diagnosed with ASD; this variant was undetectable in DNA from the blood of either parent, suggesting gonadal mosaicism of this paternally expressed gene (Soden et al., 2014). Fountain et al., 2016 reported a total of 18 newly identified individuals with Schaaf-Yang syndrome from 14 families. Of the seven newly identified cases in Fountain et al., 2016 that were formally evaluated for ASD, four cases were formally diagnosed with ASD (including two paternal cousins with a paternally-inherited frameshift variant and a case with a de novo frameshift variant); an additional six cases presented with autistic behaviors but were not formally evaluated for ASD. McCarthy et al., 2018 reported the phenotypes of an international cohort of 78 patients with nonsense or frameshift mutations in MAGEL2 (43 previously reported individuals, 35 newly identified individuals) and found that, of the 32 individuals in this cohort that had been formally evaluated for ASD using ADOS-2 and ADI-R, 25 were formally diagnosed with ASD (78%).

Reports Added
[New Scoring Scheme]
7/1/2019
2S
icon
2S

Decreased from 2S to 2S

Description

A de novo frameshift variant on the paternal allele of the MAGEL2 gene was identified in a male patient with ASD, mild intellectual disability, and a history of Prader-Willi-like phenotypes; this variant was absent in dbSNP, 1000 Genomes, and ESP5000 . A search of the Baylor College of Medicine Whole-Genome Laboratory database identified an additional three subjects with loss-of-function variants on the paternal allele of MAGEL2 (two of which were de novo) who also presented with ASD, intellectual disability, and some or all of the clinical and behavioral features of Prader-Willi syndrome (PMID 24076603). A frameshift variant in MAGEL2 (c.1996dupC;p.Gln666ProfsTer47) was identified in two siblings presenting with Schaaf-Yang syndrome, one of whom was diagnosed with ASD; this variant was undetectable in DNA from the blood of either parent, suggesting gonadal mosaicism of this paternally expressed gene (Soden et al., 2014). Fountain et al., 2016 reported a total of 18 newly identified individuals with Schaaf-Yang syndrome from 14 families. Of the seven newly identified cases in Fountain et al., 2016 that were formally evaluated for ASD, four cases were formally diagnosed with ASD (including two paternal cousins with a paternally-inherited frameshift variant and a case with a de novo frameshift variant); an additional six cases presented with autistic behaviors but were not formally evaluated for ASD. McCarthy et al., 2018 reported the phenotypes of an international cohort of 78 patients with nonsense or frameshift mutations in MAGEL2 (43 previously reported individuals, 35 newly identified individuals) and found that, of the 32 individuals in this cohort that had been formally evaluated for ASD using ADOS-2 and ADI-R, 25 were formally diagnosed with ASD (78%).

Reports Added
[MAGEL2-related disorders: A study and case series.2019]
10/1/2018
2S
icon
2S

Decreased from 2S to 2S

Description

A de novo frameshift variant on the paternal allele of the MAGEL2 gene was identified in a male patient with ASD, mild intellectual disability, and a history of Prader-Willi-like phenotypes; this variant was absent in dbSNP, 1000 Genomes, and ESP5000 . A search of the Baylor College of Medicine Whole-Genome Laboratory database identified an additional three subjects with loss-of-function variants on the paternal allele of MAGEL2 (two of which were de novo) who also presented with ASD, intellectual disability, and some or all of the clinical and behavioral features of Prader-Willi syndrome (PMID 24076603). A frameshift variant in MAGEL2 (c.1996dupC;p.Gln666ProfsTer47) was identified in two siblings presenting with Schaaf-Yang syndrome, one of whom was diagnosed with ASD; this variant was undetectable in DNA from the blood of either parent, suggesting gonadal mosaicism of this paternally expressed gene (Soden et al., 2014). Fountain et al., 2016 reported a total of 18 newly identified individuals with Schaaf-Yang syndrome from 14 families. Of the seven newly identified cases in Fountain et al., 2016 that were formally evaluated for ASD, four cases were formally diagnosed with ASD (including two paternal cousins with a paternally-inherited frameshift variant and a case with a de novo frameshift variant); an additional six cases presented with autistic behaviors but were not formally evaluated for ASD. McCarthy et al., 2018 reported the phenotypes of an international cohort of 78 patients with nonsense or frameshift mutations in MAGEL2 (43 previously reported individuals, 35 newly identified individuals) and found that, of the 32 individuals in this cohort that had been formally evaluated for ASD using ADOS-2 and ADI-R, 25 were formally diagnosed with ASD (78%).

Reports Added
[Schaaf-Yang syndrome overview: Report of 78 individuals.2018] [A Novel Mutation of MAGEL2 in a Patient with Schaaf-Yang Syndrome and Hypopituitarism.2018] [Neurocognitive and Neurobehavioral Phenotype of Youth with Schaaf-Yang Syndrome.2018]
7/1/2017
2S
icon
2S

Decreased from 2S to 2S

Description

A de novo frameshift variant on the paternal allele of the MAGEL2 gene was identified in a male patient with ASD, mild intellectual disability, and a history of Prader-Willi-like phenotypes; this variant was absent in dbSNP, 1000 Genomes, and ESP5000 . A search of the Baylor College of Medicine Whole-Genome Laboratory database identified an additional three subjects with loss-of-function variants on the paternal allele of MAGEL2 (two of which were de novo) who also presented with ASD, intellectual disability, and some or all of the clinical and behavioral features of Prader-Willi syndrome (PMID 24076603). A frameshift variant in MAGEL2 (c.1996dupC;p.Gln666ProfsTer47) was identified in two siblings presenting with Schaaf-Yang syndrome, one of whom was diagnosed with ASD; this variant was undetectable in DNA from the blood of either parent, suggesting gonadal mosaicism of this paternally expressed gene (Soden et al., 2014). Fountain et al., 2016 reported a total of 18 newly identified individuals with Schaaf-Yang syndrome from 14 families. Of the seven newly identified cases in Fountain et al., 2016 that were formally evaluated for ASD, four cases were formally diagnosed with ASD (including two paternal cousins with a paternally-inherited frameshift variant and a case with a de novo frameshift variant); an additional six cases presented with autistic behaviors but were not formally evaluated for ASD.

Reports Added
[Pitfalls of trio-based exome sequencing: imprinted genes and parental mosaicism-MAGEL2 as an example.2017]
4/1/2017
2S
icon
2S

Decreased from 2S to 2S

Description

A de novo frameshift variant on the paternal allele of the MAGEL2 gene was identified in a male patient with ASD, mild intellectual disability, and a history of Prader-Willi-like phenotypes; this variant was absent in dbSNP, 1000 Genomes, and ESP5000 . A search of the Baylor College of Medicine Whole-Genome Laboratory database identified an additional three subjects with loss-of-function variants on the paternal allele of MAGEL2 (two of which were de novo) who also presented with ASD, intellectual disability, and some or all of the clinical and behavioral features of Prader-Willi syndrome (PMID 24076603). A frameshift variant in MAGEL2 (c.1996dupC;p.Gln666ProfsTer47) was identified in two siblings presenting with Schaaf-Yang syndrome, one of whom was diagnosed with ASD; this variant was undetectable in DNA from the blood of either parent, suggesting gonadal mosaicism of this paternally expressed gene (Soden et al., 2014). Fountain et al., 2016 reported a total of 18 newly identified individuals with Schaaf-Yang syndrome from 14 families. Of the seven newly identified cases in Fountain et al., 2016 that were formally evaluated for ASD, four cases were formally diagnosed with ASD (including two paternal cousins with a paternally-inherited frameshift variant and a case with a de novo frameshift variant); an additional six cases presented with autistic behaviors but were not formally evaluated for ASD.

Reports Added
[Truncating mutations of MAGEL2 cause Prader-Willi phenotypes and autism.2013] [Truncating Mutations of MAGEL2, a Gene within the Prader-Willi Locus, Are Responsible for Severe Arthrogryposis.2015] [The phenotypic spectrum of Schaaf-Yang syndrome: 18 new affected individuals from 14 families.2016] [Effectiveness of exome and genome sequencing guided by acuity of illness for diagnosis of neurodevelopmental disorders.2014] [Loss of Magel2 impairs the development of hypothalamic Anorexigenic circuits.2016] [Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability2016] [Clinical exome sequencing: results from 2819 samples reflecting 1000 families.2016] [A De Novo Nonsense Mutation in MAGEL2 in a Patient Initially Diagnosed as Opitz-C: Similarities Between Schaaf-Yang and Opitz-C Syndromes.2017] [Genomic diagnosis for children with intellectual disability and/or developmental delay.2017]
10/1/2016
2S
icon
2S

Decreased from 2S to 2S

Description

A de novo frameshift variant on the paternal allele of the MAGEL2 gene was identified in a male patient with ASD, mild intellectual disability, and a history of Prader-Willi-like phenotypes; this variant was absent in dbSNP, 1000 Genomes, and ESP5000 . A search of the Baylor College of Medicine Whole-Genome Laboratory database identified an additional three subjects with loss-of-function variants on the paternal allele of MAGEL2 (two of which were de novo) who also presented with ASD, intellectual disability, and some or all of the clinical and behavioral features of Prader-Willi syndrome (PMID 24076603). A frameshift variant in MAGEL2 (c.1996dupC;p.Gln666ProfsTer47) was identified in two siblings presenting with Schaaf-Yang syndrome, one of whom was diagnosed with ASD; this variant was undetectable in DNA from the blood of either parent, suggesting gonadal mosaicism of this paternally expressed gene (Soden et al., 2014). Fountain et al., 2016 reported a total of 18 newly identified individuals with Schaaf-Yang syndrome from 14 families. Of the seven newly identified cases in Fountain et al., 2016 that were formally evaluated for ASD, four cases were formally diagnosed with ASD (including two paternal cousins with a paternally-inherited frameshift variant and a case with a de novo frameshift variant); an additional six cases presented with autistic behaviors but were not formally evaluated for ASD.

Reports Added
[Clinical exome sequencing: results from 2819 samples reflecting 1000 families.2016]
7/1/2016
2S
icon
2S

Decreased from 2S to 2S

Description

A de novo frameshift variant on the paternal allele of the MAGEL2 gene was identified in a male patient with ASD, mild intellectual disability, and a history of Prader-Willi-like phenotypes; this variant was absent in dbSNP, 1000 Genomes, and ESP5000 . A search of the Baylor College of Medicine Whole-Genome Laboratory database identified an additional three subjects with loss-of-function variants on the paternal allele of MAGEL2 (two of which were de novo) who also presented with ASD, intellectual disability, and some or all of the clinical and behavioral features of Prader-Willi syndrome (PMID 24076603). A frameshift variant in MAGEL2 (c.1996dupC;p.Gln666ProfsTer47) was identified in two siblings presenting with Schaaf-Yang syndrome, one of whom was diagnosed with ASD; this variant was undetectable in DNA from the blood of either parent, suggesting gonadal mosaicism of this paternally expressed gene (Soden et al., 2014). Fountain et al., 2016 reported a total of 18 newly identified individuals with Schaaf-Yang syndrome from 14 families. Of the seven newly identified cases in Fountain et al., 2016 that were formally evaluated for ASD, four cases were formally diagnosed with ASD (including two paternal cousins with a paternally-inherited frameshift variant and a case with a de novo frameshift variant); an additional six cases presented with autistic behaviors but were not formally evaluated for ASD.

Reports Added
[Loss of Magel2 impairs the development of hypothalamic Anorexigenic circuits.2016] [Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability2016]
4/1/2016
2S
icon
2S

Decreased from 2S to 2S

Description

A de novo frameshift variant on the paternal allele of the MAGEL2 gene was identified in a male patient with ASD, mild intellectual disability, and a history of Prader-Willi-like phenotypes; this variant was absent in dbSNP, 1000 Genomes, and ESP5000 . A search of the Baylor College of Medicine Whole-Genome Laboratory database identified an additional three subjects with loss-of-function variants on the paternal allele of MAGEL2 (two of which were de novo) who also presented with ASD, intellectual disability, and some or all of the clinical and behavioral features of Prader-Willi syndrome (PMID 24076603). A frameshift variant in MAGEL2 (c.1996dupC;p.Gln666ProfsTer47) was identified in two siblings presenting with Schaaf-Yang syndrome, one of whom was diagnosed with ASD; this variant was undetectable in DNA from the blood of either parent, suggesting gonadal mosaicism of this paternally expressed gene (Soden et al., 2014). Fountain et al., 2016 reported a total of 18 newly identified individuals with Schaaf-Yang syndrome from 14 families. Of the seven newly identified cases in Fountain et al., 2016 that were formally evaluated for ASD, four cases were formally diagnosed with ASD (including two paternal cousins with a paternally-inherited frameshift variant and a case with a de novo frameshift variant); an additional six cases presented with autistic behaviors but were not formally evaluated for ASD.

Reports Added
[Truncating mutations of MAGEL2 cause Prader-Willi phenotypes and autism.2013] [Truncating Mutations of MAGEL2, a Gene within the Prader-Willi Locus, Are Responsible for Severe Arthrogryposis.2015] [The phenotypic spectrum of Schaaf-Yang syndrome: 18 new affected individuals from 14 families.2016] [Effectiveness of exome and genome sequencing guided by acuity of illness for diagnosis of neurodevelopmental disorders.2014]
1/1/2016
2S
icon
2S

Decreased from 2S to 2S

Description

A de novo frameshift variant on the paternal allele of the MAGEL2 gene was identified in a male patient with ASD, mild intellectual disability, and a history of Prader-Willi-like phenotypes; this variant was absent in dbSNP, 1000 Genomes, and ESP5000 . A search of the Baylor College of Medicine Whole-Genome Laboratory database identified an additional three subjects with loss-of-function variants on the paternal allele of MAGEL2 (two of which were de novo) who also presented with ASD, intellectual disability, and some or all of the clinical and behavioral features of Prader-Willi syndrome (PMID 24076603).

Reports Added
[Truncating mutations of MAGEL2 cause Prader-Willi phenotypes and autism.2013] [Truncating Mutations of MAGEL2, a Gene within the Prader-Willi Locus, Are Responsible for Severe Arthrogryposis.2015]
4/1/2015
icon
2S

Increased from to 2S

Description

A de novo frameshift variant on the paternal allele of the MAGEL2 gene was identified in a male patient with ASD, mild intellectual disability, and a history of Prader-Willi-like phenotypes; this variant was absent in dbSNP, 1000 Genomes, and ESP5000 . A search of the Baylor College of Medicine Whole-Genome Laboratory database identified an additional three subjects with loss-of-function variants on the paternal allele of MAGEL2 (two of which were de novo) who also presented with ASD, intellectual disability, and some or all of the clinical and behavioral features of Prader-Willi syndrome (PMID 24076603).

Krishnan Probability Score

Score 0.60479047652504

Ranking 343/25841 scored genes


[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning approach on a human brain-specific gene network. The method was first presented in Nat Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed in column G of supplementary table 3 (see: http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at asd.princeton.edu.
Original Source
ExAC Score

Score 0.92241126903557

Ranking 3010/18225 scored genes


[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of- function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of- function mutations in autism in such a gene would be more likely to confer risk. For a full list of pLI scores see: ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle aned_exac_nonTCGA_z_pli_rec_null_data.txt
Original Source
Sanders TADA Score

Score 0.93464987434279

Ranking 12633/18665 scored genes


[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013), and is a statistic that integrates evidence from both de novo and transmitted mutations. It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233 (2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper (the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Original Source
Larsen Cumulative Evidence Score

Score 38

Ranking 54/461 scored genes


[Show Scoring Methodology]
Larsen and colleagues generated gene scores based on the sum of evidence for all available ASD-associated variants in a gene, with assessments based on mode of inheritance, effect size, and variant frequency in the general population. The approach was first presented in Mol Autism 7:44 (2016), and scores for 461 genes can be found in column I in supplementary table 4 from that paper.
Original Source
Zhang D Score

Score 0.14940069206688

Ranking 5189/20870 scored genes


[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures), or D score, was developed to combine evidence from de novo loss-of- function mutation with evidence from cell-type- specific gene expression in the mouse brain (specifically translational profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with positive D scores are more likely to be associated with autism risk, with higher-confidence genes having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204- 215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in supplementary table 2 from that paper.
Original Source
CNVs associated with MAGEL2(1 CNVs)
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15q11.2 114 Deletion-Duplication 153  /  2238
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