#618825
Table of Contents
A number sign (#) is used with this entry because of evidence that autosomal dominant intellectual developmental disorder-63 with macrocephaly (MRD63) is caused by heterozygous mutation in the TRIO gene (601893) on chromosome 5p15.
Heterozygous mutation in the TRIO gene can also cause a similar disorder with microcephaly (MRD44; 617061).
Barbosa et al. (2020) reported 9 unrelated patients with MRD63. One of the patients (patient 9) had previously been reported by Pengelly et al. (2016). Most of the patients ranged in age from 3 to 19 years; 1 was 40 years old. All had global developmental delay with delayed walking usually by 3 to 5 years of age, although 3 younger patients were unable to walk independently. They had moderate (2 patients) or severe (7 patients) impaired intellectual development with poor or absent speech, expressive and comprehensive language delay, and variable behavioral abnormalities, such as stereotypies. Two patients had seizures and 1 had possible EEG abnormalities. Overall growth was generally poor, and many had early feeding difficulties, although all except 2 had relative macrocephaly (+2 to +4.7 SD). About half of the patients had variable dysmorphic features, including high forehead with frontal bossing, arched eyebrows, long or downslanting palpebral fissures, low hanging columella, high nasal bridge, hypoplastic or anteverted nares, large earlobes, large mouth, and thin upper lip. Less common features included dental anomalies, short tapering digits, small hands and feet, and scoliosis.
The heterozygous mutations in the TRIO gene that were identified in patients with MRD63 by Barbosa et al. (2020) occurred de novo.
In 9 unrelated patients with MRD63, Barbosa et al. (2020) identified 5 different heterozygous missense mutations in the TRIO gene (see, e.g., 601893.0007-601893.0010). The mutations, which were found by exome sequencing, were confirmed to occur de novo in 8 patients; inheritance was unknown in the ninth patient. All mutations occurred at highly conserved residues in the seventh spectrin repeat, and none were present in the gnomAD database. Three mutations, found in 6 unrelated patients, affected the same residue (R1078W, R1078G, and R1078Q). Molecular modeling predicted that the mutations could cause steric hindrance and alter the structural organization of the protein or interfere with protein folding. Expression of the mutations into HEK293 cells resulted in increased RAC1 (602048) activation, as measured by increased PAK1 (602590) phosphorylation, compared to wildtype. Transfection of the mutations into neuroblastoma cells caused enhanced neurite outgrowth and increased lamellipodia formation compared to controls. The findings were consistent with a gain-of-function effect.
Barbosa, S., Greville-Heygate, S. Bonnet, M., Godwin, A., Fagotto-Kaufmann, C., Kajava, A. V., Laouteouet, D., Mawby, R., Wai, H. A., Dingemans, A. J. M., Hehir-Kwa, J., Willems, M., and 32 others. Opposite modulation of RAC2 by mutations in TRIO is associated with distinct, domain-specific neurodevelopmental disorders. Am. J. Hum. Genet. 106: 338-355, 2020. [PubMed: 32109419, images, related citations] [Full Text]
Pengelly, R. J., Greville-Heygate, S., Schmidt, S., Seaby, E. G., Jabalameli, M. R., Mehta, S. G. Parker, M. J., Goudie, D., Fagotto-Kaufmann, C., Mercer, C., the DDD Study, Debant, A., Ennis, S., Baralle, D. Mutations specific to the Rac-GEF domain of TRIO cause intellectual disability and microcephaly. J. Med. Genet. 53: 735-742, 2016. [PubMed: 27418539, images, related citations] [Full Text]
Alternative titles; symbols
DO: 0061036;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 5p15.2 | Intellectual developmental disorder, autosomal dominant 63, with macrocephaly | 618825 | Autosomal dominant | 3 | TRIO | 601893 |
A number sign (#) is used with this entry because of evidence that autosomal dominant intellectual developmental disorder-63 with macrocephaly (MRD63) is caused by heterozygous mutation in the TRIO gene (601893) on chromosome 5p15.
Heterozygous mutation in the TRIO gene can also cause a similar disorder with microcephaly (MRD44; 617061).
Barbosa et al. (2020) reported 9 unrelated patients with MRD63. One of the patients (patient 9) had previously been reported by Pengelly et al. (2016). Most of the patients ranged in age from 3 to 19 years; 1 was 40 years old. All had global developmental delay with delayed walking usually by 3 to 5 years of age, although 3 younger patients were unable to walk independently. They had moderate (2 patients) or severe (7 patients) impaired intellectual development with poor or absent speech, expressive and comprehensive language delay, and variable behavioral abnormalities, such as stereotypies. Two patients had seizures and 1 had possible EEG abnormalities. Overall growth was generally poor, and many had early feeding difficulties, although all except 2 had relative macrocephaly (+2 to +4.7 SD). About half of the patients had variable dysmorphic features, including high forehead with frontal bossing, arched eyebrows, long or downslanting palpebral fissures, low hanging columella, high nasal bridge, hypoplastic or anteverted nares, large earlobes, large mouth, and thin upper lip. Less common features included dental anomalies, short tapering digits, small hands and feet, and scoliosis.
The heterozygous mutations in the TRIO gene that were identified in patients with MRD63 by Barbosa et al. (2020) occurred de novo.
In 9 unrelated patients with MRD63, Barbosa et al. (2020) identified 5 different heterozygous missense mutations in the TRIO gene (see, e.g., 601893.0007-601893.0010). The mutations, which were found by exome sequencing, were confirmed to occur de novo in 8 patients; inheritance was unknown in the ninth patient. All mutations occurred at highly conserved residues in the seventh spectrin repeat, and none were present in the gnomAD database. Three mutations, found in 6 unrelated patients, affected the same residue (R1078W, R1078G, and R1078Q). Molecular modeling predicted that the mutations could cause steric hindrance and alter the structural organization of the protein or interfere with protein folding. Expression of the mutations into HEK293 cells resulted in increased RAC1 (602048) activation, as measured by increased PAK1 (602590) phosphorylation, compared to wildtype. Transfection of the mutations into neuroblastoma cells caused enhanced neurite outgrowth and increased lamellipodia formation compared to controls. The findings were consistent with a gain-of-function effect.
Barbosa, S., Greville-Heygate, S. Bonnet, M., Godwin, A., Fagotto-Kaufmann, C., Kajava, A. V., Laouteouet, D., Mawby, R., Wai, H. A., Dingemans, A. J. M., Hehir-Kwa, J., Willems, M., and 32 others. Opposite modulation of RAC2 by mutations in TRIO is associated with distinct, domain-specific neurodevelopmental disorders. Am. J. Hum. Genet. 106: 338-355, 2020. [PubMed: 32109419] [Full Text: https://doi.org/10.1016/j.ajhg.2020.01.018]
Pengelly, R. J., Greville-Heygate, S., Schmidt, S., Seaby, E. G., Jabalameli, M. R., Mehta, S. G. Parker, M. J., Goudie, D., Fagotto-Kaufmann, C., Mercer, C., the DDD Study, Debant, A., Ennis, S., Baralle, D. Mutations specific to the Rac-GEF domain of TRIO cause intellectual disability and microcephaly. J. Med. Genet. 53: 735-742, 2016. [PubMed: 27418539] [Full Text: https://doi.org/10.1136/jmedgenet-2016-103942]
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