Truncating variants of the DLG4 gene are responsible for intellectual disability with marfanoid features.

S. Moutton, A.-L. Bruel, M. Assoum, M. Chevarin, E. Sarrazin, C. Goizet, A.-M. Guerrot, A. Charollais, P. Charles, D. Heron, A. Faudet, N. Houcinat, A. Vitobello, F. Tran-Mau-Them, C. Philippe, Y. Duffourd, C. Thauvin-Robinet, L. Faivre
Clinical Genetics. 2018-04-14; 93(6): 1172-1178
DOI: 10.1111/cge.13243

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1. Clin Genet. 2018 Jun;93(6):1172-1178. doi: 10.1111/cge.13243. Epub 2018 Apr 14.

Truncating variants of the DLG4 gene are responsible for intellectual disability
with marfanoid features.

Moutton S(1)(2), Bruel AL(2), Assoum M(2), Chevarin M(2), Sarrazin E(3), Goizet
C(4), Guerrot AM(5), Charollais A(6), Charles P(7), Heron D(7), Faudet A(7),
Houcinat N(1)(2), Vitobello A(2), Tran-Mau-Them F(1)(2), Philippe C(1)(2),
Duffourd Y(2), Thauvin-Robinet C(1)(2), Faivre L(1)(2).

Author information:
(1)Reference Center for Developmental Anomalies, Department of Medical Genetics,
Dijon University Hospital, Dijon, France.
(2)INSERM U1231, LNC UMR1231 GAD, Burgundy University, Dijon, France.
(3)Caribbean Reference Center for Rare Neurological and Neuromuscular Diseases,
Fort de France University Hospital, Fort de France, France.
(4)Reference Center for Developmental Anomalies, Medical Genetics Department, CHU
Bordeaux and Laboratoire MRGM, INSERM U1211, University of Bordeaux, Bordeaux,
(5)Department of Genetics, Rouen University Hospital, Rouen, France.
(6)Department of Neonatal Medicine and Intensive Care, Neuropediatrics and
Reference Centre for Learning Disabilities, Rouen University Hospital, Rouen,
(7)Reference Center for Rare Intellectual Disability Disorders, AP-HP,
Pitié-Salpêtrière Hospital, Paris, France and Clinical Research Group
“intellectual disability and autism”, UPMC, Paris, France.

Marfanoid habitus (MH) combined with intellectual disability (ID) is a
genetically and clinically heterogeneous group of overlapping disorders. We
performed exome sequencing in 33 trios and 31 single probands to identify novel
genes specific to MH-ID. After the search for variants in known disease-causing
genes and non-disease-causing genes with classical approaches, we searched for
variants in non-disease-causing genes whose pLI was above 0.9 (ExAC Consortium
data), in which truncating variants were found in at least 3 unrelated patients.
Only DLG4 gene met these criteria. Data from the literature and various databases
also indicated its implication in ID. DLG4 encodes post-synaptic density protein
95 (PSD-95), a protein expressed in various tissues, including the brain. In
neurons, PSD-95 is located at the post-synaptic density, and is associated with
glutamatergic receptor signaling (NMDA and AMPA). PSD-95 probably participates in
dendritogenesis. Two patients were heterozygous for de novo frameshift variants
and one patient carried a a consensus splice site variant. Gene expression
studies supported their pathogenicity through haploinsufficiency and
loss-of-function. Patients exhibited mild-to-moderate ID, similar marfanoid
features, including a long face, high-arched palate, long and thin fingers,
pectus excavatum, scoliosis and ophthalmological manifestations (nystagmus or
strabismus). Our study emphasizes the role of DLG4 as a novel
post-synaptic-associated gene involved in syndromic ID associated with MH.

© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

DOI: 10.1111/cge.13243
PMID: 29460436 [Indexed for MEDLINE]

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