Abstract
Dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 1 A (DYRK1A) maps to the Down syndrome critical region; copy number increase of this gene is thought to have a major role in the neurocognitive deficits associated with Trisomy 21. Truncation of DYRK1A in patients with developmental delay (DD) and autism spectrum disorder (ASD) suggests a different pathology associated with loss-of-function mutations. To understand the phenotypic spectrum associated with DYRK1A mutations, we resequenced the gene in 7162 ASD/DD patients (2446 previously reported) and 2169 unaffected siblings and performed a detailed phenotypic assessment on nine patients. Comparison of our data and published cases with 8696 controls identified a significant enrichment of DYRK1A truncating mutations (P=0.00851) and an excess of de novo mutations (P=2.53 × 10-10) among ASD/intellectual disability (ID) patients. Phenotypic comparison of all novel (n=5) and recontacted (n=3) cases with previous case reports, including larger CNV and translocation events (n=7), identified a syndromal disorder among the 15 patients. It was characterized by ID, ASD, microcephaly, intrauterine growth retardation, febrile seizures in infancy, impaired speech, stereotypic behavior, hypertonia and a specific facial gestalt. We conclude that mutations in DYRK1A define a syndromic form of ASD and ID with neurodevelopmental defects consistent with murine and Drosophila knockout models.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 126-132 |
| Number of pages | 7 |
| Journal | Molecular Psychiatry |
| Volume | 21 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jan 1 2016 |
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ASJC Scopus subject areas
- Molecular Biology
- Psychiatry and Mental health
- Cellular and Molecular Neuroscience
Cite this
Disruptive de novo mutations of DYRK1A lead to a syndromic form of autism and ID. / Van Bon, B. W M; Coe, B. P.; Bernier, R.; Green, C.; Gerdts, J.; Witherspoon, K.; Kleefstra, T.; Willemsen, M. H.; Kumar, R.; Bosco, P.; Fichera, M.; Li, D.; Amaral, David G; Cristofoli, F.; Peeters, H.; Haan, E.; Romano, C.; Mefford, H. C.; Scheffer, I.; Gecz, J.; De Vries, B. B A; Eichler, E. E.
In: Molecular Psychiatry, Vol. 21, No. 1, 01.01.2016, p. 126-132.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Disruptive de novo mutations of DYRK1A lead to a syndromic form of autism and ID
AU - Van Bon, B. W M
AU - Coe, B. P.
AU - Bernier, R.
AU - Green, C.
AU - Gerdts, J.
AU - Witherspoon, K.
AU - Kleefstra, T.
AU - Willemsen, M. H.
AU - Kumar, R.
AU - Bosco, P.
AU - Fichera, M.
AU - Li, D.
AU - Amaral, David G
AU - Cristofoli, F.
AU - Peeters, H.
AU - Haan, E.
AU - Romano, C.
AU - Mefford, H. C.
AU - Scheffer, I.
AU - Gecz, J.
AU - De Vries, B. B A
AU - Eichler, E. E.
PY - 2016/1/1
Y1 - 2016/1/1
N2 - Dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 1 A (DYRK1A) maps to the Down syndrome critical region; copy number increase of this gene is thought to have a major role in the neurocognitive deficits associated with Trisomy 21. Truncation of DYRK1A in patients with developmental delay (DD) and autism spectrum disorder (ASD) suggests a different pathology associated with loss-of-function mutations. To understand the phenotypic spectrum associated with DYRK1A mutations, we resequenced the gene in 7162 ASD/DD patients (2446 previously reported) and 2169 unaffected siblings and performed a detailed phenotypic assessment on nine patients. Comparison of our data and published cases with 8696 controls identified a significant enrichment of DYRK1A truncating mutations (P=0.00851) and an excess of de novo mutations (P=2.53 × 10-10) among ASD/intellectual disability (ID) patients. Phenotypic comparison of all novel (n=5) and recontacted (n=3) cases with previous case reports, including larger CNV and translocation events (n=7), identified a syndromal disorder among the 15 patients. It was characterized by ID, ASD, microcephaly, intrauterine growth retardation, febrile seizures in infancy, impaired speech, stereotypic behavior, hypertonia and a specific facial gestalt. We conclude that mutations in DYRK1A define a syndromic form of ASD and ID with neurodevelopmental defects consistent with murine and Drosophila knockout models.
AB - Dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 1 A (DYRK1A) maps to the Down syndrome critical region; copy number increase of this gene is thought to have a major role in the neurocognitive deficits associated with Trisomy 21. Truncation of DYRK1A in patients with developmental delay (DD) and autism spectrum disorder (ASD) suggests a different pathology associated with loss-of-function mutations. To understand the phenotypic spectrum associated with DYRK1A mutations, we resequenced the gene in 7162 ASD/DD patients (2446 previously reported) and 2169 unaffected siblings and performed a detailed phenotypic assessment on nine patients. Comparison of our data and published cases with 8696 controls identified a significant enrichment of DYRK1A truncating mutations (P=0.00851) and an excess of de novo mutations (P=2.53 × 10-10) among ASD/intellectual disability (ID) patients. Phenotypic comparison of all novel (n=5) and recontacted (n=3) cases with previous case reports, including larger CNV and translocation events (n=7), identified a syndromal disorder among the 15 patients. It was characterized by ID, ASD, microcephaly, intrauterine growth retardation, febrile seizures in infancy, impaired speech, stereotypic behavior, hypertonia and a specific facial gestalt. We conclude that mutations in DYRK1A define a syndromic form of ASD and ID with neurodevelopmental defects consistent with murine and Drosophila knockout models.
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U2 - 10.1038/mp.2015.5
DO - 10.1038/mp.2015.5
M3 - Article
C2 - 25707398
AN - SCOPUS:84951908030
VL - 21
SP - 126
EP - 132
JO - Molecular Psychiatry
JF - Molecular Psychiatry
SN - 1359-4184
IS - 1
ER -