#618793
Table of Contents
A number sign (#) is used with this entry because of evidence that autosomal dominant intellectual developmental disorder-62 (MRD62) is caused by heterozygous mutation in the DLG4 gene (602887) on chromosome 17p13.
Lelieveld et al. (2016) reported 3 unrelated patients with MRD62. Clinical details were limited, but all had mildly to moderately impaired intellectual development and motor delay. Two patients each had language delay, nonspecific dysmorphic facial features, and visual impairment; 1 patient had behavioral abnormalities.
Moutton et al. (2018) reported 3 unrelated French men, ranging in age from 31 to 35 years, with MRD62. The patients had normal or only mildly delayed early development, with normal acquisition of walking or walking by age 3 years, and mildly to moderately impaired intellectual development (IQ of 56 in 1 patient). All had attended special schools. Two patients spoke and were able to read and write, including 1 who worked at a vocational job, whereas 1 patient (patient 3) was more severely affected with inability to read or write and very poor language. This patient, who also had autism spectrum disorder, developed seizures at age 14 years. Brain imaging was normal in 1 patient and showed mild cerebellar vermis or subcortical atrophy in the others. The patients also showed some marfanoid features, although none had aortic dilation, ectopia lentis, or myopia. The variable features included highly arched palate, long face, long thin fingers, pectus or foot deformities, and mild scoliosis. Two patients had mild joint hyperlaxity, 2 had strabismus, 1 had nystagmus, 2 had mild pyramidal signs and motor clumsiness, and 1 had umbilical hernia.
The heterozygous mutations in the DLG4 gene that were identified in patients with MRD62 by Lelieveld et al. (2016) and Moutton et al. (2018) occurred de novo.
In 3 unrelated patients with MRD62, Lelieveld et al. (2016) identified 3 different de novo heterozygous frameshift or nonsense mutations in the DLG4 gene (602887.0001-602887.0003). The mutations, which were found by trio-based exome sequencing and confirmed by Sanger sequencing, were not found in the dbSNP (build 137) database. Functional studies of the variants and studies of patient cells were not performed, but all variants were predicted to result in haploinsufficiency. The patients were ascertained from a cohort of 820 individuals with intellectual disability who underwent trio-based exome sequencing.
In 3 unrelated adult males with MRD62, Moutton et al. (2018) identified heterozygous loss-of-function mutations in the DLG4 gene (602887.0004-602887.0006). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, were not found in public databases, including gnomAD. The mutations occurred de novo in 2 patients; paternal DNA from the third patient was not available. Analysis of cells derived from 2 patients showed a 50% decrease in mRNA, suggesting that the mutation resulted in nonsense-mediated mRNA decay. Cells derived from the third patient, who had a splice site mutation, suggested production of an abnormal mRNA that would result in premature protein termination. The patients were ascertained from a cohort of 64 individuals with intellectual disability who also had some clinical marfanoid features.
Feyder et al. (2010) found that Dlg4-null mice showed increased repetitive behaviors, abnormal communication and social behaviors, impaired motor coordination, and increased stress reactivity and anxiety-related responses compared to controls. Mutant mice also had subtle morphologic dendritic anomalies in the basolateral amygdala and altered forebrain expression of various synaptic genes. The phenotypic findings were reminiscent of autism spectrum disorders.
Feyder, M., Karlsson, R.-M., Mathur, P., Lyman, M., Bock, R., Momenan, R., Munasinghe, J., Scattoni, M. L., Ihne, J., Camp, M., Graybeal, C., Strathdee, D., and 9 others. Association of mouse Dlg4 (PSD-95) gene deletion and human DLG4 gene variation with phenotypes relevant to autism spectrum disorders and Williams' syndrome. Am. J. Psychiat. 167: 1508-1517, 2010. [PubMed: 20952458, images, related citations] [Full Text]
Lelieveld, S. H., Reijnders, M. R. F., Pfundt, R., Yntema, H. G., Kamsteeg, E.-J., de Vries, P., de Vries, B. B. A., Willemsen, M. H., Kleefstra, T., Lohner, K., Vreeburg, M., Stevens, S. J. C., and 10 others. Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability. Nature Neurosci. 19: 1194-1196, 2016. [PubMed: 27479843, related citations] [Full Text]
Moutton, S., Bruel, A.-L., Assoum, M., Chevarin, M., Sarrazin, E., Goizet, C., Guerrot, A. M., Charollais, A., Charles, P., Heron, D., Faudet, A., Houcinat, N., Vitobello, A., Tran-Mau-Them, F., Philippe, C., Duffourd, Y., Thauvin-Robinet, C., Faivre, L. Truncating variants of the DLG4 gene are responsible for intellectual disability with marfanoid features. Clin. Genet. 93: 1172-1178, 2018. [PubMed: 29460436, related citations] [Full Text]
Alternative titles; symbols
DO: 0061035;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 17p13.1 | Intellectual developmental disorder, autosomal dominant 62 | 618793 | Autosomal dominant | 3 | DLG4 | 602887 |
A number sign (#) is used with this entry because of evidence that autosomal dominant intellectual developmental disorder-62 (MRD62) is caused by heterozygous mutation in the DLG4 gene (602887) on chromosome 17p13.
Lelieveld et al. (2016) reported 3 unrelated patients with MRD62. Clinical details were limited, but all had mildly to moderately impaired intellectual development and motor delay. Two patients each had language delay, nonspecific dysmorphic facial features, and visual impairment; 1 patient had behavioral abnormalities.
Moutton et al. (2018) reported 3 unrelated French men, ranging in age from 31 to 35 years, with MRD62. The patients had normal or only mildly delayed early development, with normal acquisition of walking or walking by age 3 years, and mildly to moderately impaired intellectual development (IQ of 56 in 1 patient). All had attended special schools. Two patients spoke and were able to read and write, including 1 who worked at a vocational job, whereas 1 patient (patient 3) was more severely affected with inability to read or write and very poor language. This patient, who also had autism spectrum disorder, developed seizures at age 14 years. Brain imaging was normal in 1 patient and showed mild cerebellar vermis or subcortical atrophy in the others. The patients also showed some marfanoid features, although none had aortic dilation, ectopia lentis, or myopia. The variable features included highly arched palate, long face, long thin fingers, pectus or foot deformities, and mild scoliosis. Two patients had mild joint hyperlaxity, 2 had strabismus, 1 had nystagmus, 2 had mild pyramidal signs and motor clumsiness, and 1 had umbilical hernia.
The heterozygous mutations in the DLG4 gene that were identified in patients with MRD62 by Lelieveld et al. (2016) and Moutton et al. (2018) occurred de novo.
In 3 unrelated patients with MRD62, Lelieveld et al. (2016) identified 3 different de novo heterozygous frameshift or nonsense mutations in the DLG4 gene (602887.0001-602887.0003). The mutations, which were found by trio-based exome sequencing and confirmed by Sanger sequencing, were not found in the dbSNP (build 137) database. Functional studies of the variants and studies of patient cells were not performed, but all variants were predicted to result in haploinsufficiency. The patients were ascertained from a cohort of 820 individuals with intellectual disability who underwent trio-based exome sequencing.
In 3 unrelated adult males with MRD62, Moutton et al. (2018) identified heterozygous loss-of-function mutations in the DLG4 gene (602887.0004-602887.0006). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, were not found in public databases, including gnomAD. The mutations occurred de novo in 2 patients; paternal DNA from the third patient was not available. Analysis of cells derived from 2 patients showed a 50% decrease in mRNA, suggesting that the mutation resulted in nonsense-mediated mRNA decay. Cells derived from the third patient, who had a splice site mutation, suggested production of an abnormal mRNA that would result in premature protein termination. The patients were ascertained from a cohort of 64 individuals with intellectual disability who also had some clinical marfanoid features.
Feyder et al. (2010) found that Dlg4-null mice showed increased repetitive behaviors, abnormal communication and social behaviors, impaired motor coordination, and increased stress reactivity and anxiety-related responses compared to controls. Mutant mice also had subtle morphologic dendritic anomalies in the basolateral amygdala and altered forebrain expression of various synaptic genes. The phenotypic findings were reminiscent of autism spectrum disorders.
Feyder, M., Karlsson, R.-M., Mathur, P., Lyman, M., Bock, R., Momenan, R., Munasinghe, J., Scattoni, M. L., Ihne, J., Camp, M., Graybeal, C., Strathdee, D., and 9 others. Association of mouse Dlg4 (PSD-95) gene deletion and human DLG4 gene variation with phenotypes relevant to autism spectrum disorders and Williams' syndrome. Am. J. Psychiat. 167: 1508-1517, 2010. [PubMed: 20952458] [Full Text: https://doi.org/10.1176/appi.ajp.2010.10040484]
Lelieveld, S. H., Reijnders, M. R. F., Pfundt, R., Yntema, H. G., Kamsteeg, E.-J., de Vries, P., de Vries, B. B. A., Willemsen, M. H., Kleefstra, T., Lohner, K., Vreeburg, M., Stevens, S. J. C., and 10 others. Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability. Nature Neurosci. 19: 1194-1196, 2016. [PubMed: 27479843] [Full Text: https://doi.org/10.1038/nn.4352]
Moutton, S., Bruel, A.-L., Assoum, M., Chevarin, M., Sarrazin, E., Goizet, C., Guerrot, A. M., Charollais, A., Charles, P., Heron, D., Faudet, A., Houcinat, N., Vitobello, A., Tran-Mau-Them, F., Philippe, C., Duffourd, Y., Thauvin-Robinet, C., Faivre, L. Truncating variants of the DLG4 gene are responsible for intellectual disability with marfanoid features. Clin. Genet. 93: 1172-1178, 2018. [PubMed: 29460436] [Full Text: https://doi.org/10.1111/cge.13243]
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