#618221
Table of Contents
A number sign (#) is used with this entry because of evidence that autosomal recessive intellectual developmental disorder-66 (MRT66) is caused by homozygous mutation in the C12ORF4 gene (616082) on chromosome 12p13.
MRT66 is a nonsyndromic autosomal recessive intellectual developmental disorder with delayed speech development, neuropsychiatric symptoms, and relatively normal life span (Philips et al., 2017).
Alazami et al. (2015) reported a 12-year-old boy and his 8-year-old sister, born of first-cousin Saudi Arabian parents, with MRT66. The boy was more than 2 years of age when he walked, and had single-syllable words at 1 year, although his speech was incomprehensible at the age of 12. MRI showed nonspecific foci at high signal intensities scattered in the white matter of both cerebral hemispheres. Six years later, MRI showed interval stable appearance with multiple T2 intensities in the white matter. His sister was similarly affected. Physical exam showed subtle dysmorphic features in the form of epicanthal folds, pointed nasal tip, and exaggerated antihelix. He also had mild hyperlaxity, hypotonia, normal strength and reflexes, 2 hypopigmented patches, and 1 hyperpigmented patch.
Philips et al. (2017) reported 2 Finnish families segregating autosomal recessive mild to severe nonsyndromic intellectual disability with mutation in the C12ORF4 gene. These 2 families were found to have common ancestors in the mid to late 18th century. Five males and 2 females ranging in age from 46 to 65 years were reported. All had delayed speech development, and 1 had gait abnormalities. There were no significant dysmorphic features. The intellectual disability phenotype was milder in females. Philips et al. (2017) also reported a Dutch female from a consanguineous family with a complex insertion/deletion in C12ORF4. When evaluated at age 10 years she had moderate intellectual disability, autism spectrum disorder, and delayed speech development. Mild dysmorphic features including a long philtrum and full lips, as well as hyperlaxity, were present. Her hands were small and her gait was described as stiff and asymmetric. Brain MRI at age 6 years showed slightly increased T2 signal intensity of the cerebral white matter. Philips et al. (2017) also reported the sibs with MRT66 originally reported by Alazami et al. (2015).
Reuter et al. (2017) reported a consanguineous Turkish family (MR114) with 2 affected sibs with MRT66. The only phenotype described was that of moderate intellectual disability.
In affected sibs from a consanguineous Saudi family with an autosomal recessive intellectual developmental disorder, Alazami et al. (2015) detected homozygosity for a 4-basepair insertion in the C12ORF4 gene (616082.0001) resulting in frameshift.
In affected members of 2 distantly related Finnish families with MRT66, Philips et al. (2017) reported a homozygous missense mutation (L328P; 616082.0002) in the C12ORF4 gene. This variant was found at a frequency of 1 in 53 among blood donors from a northeastern subisolate of Finland.
Reuter et al. (2017) reported homozygosity for a nonsense mutation in the C12ORF4 gene (R454X; 616082.0003) in affected members of a consanguineous Turkish family presenting with moderately impaired intellectual development.
Alazami, A. M., Patel, N., Shamseldin, H. E., Anazi, S., Al-Dosari, M. S., Alzahrani, F., Hijazi, H., Alshammari, M., Aldahmesh, M. A., Salih, M. A., Faqeih, E., Alhashem, A., and 41 others. Accelerating novel candidate gene discovery in neurogenetic disorders via whole-exome sequencing of prescreened multiplex consanguineous families. Cell Rep. 10: 148-161, 2015. [PubMed: 25558065, related citations] [Full Text]
Philips, A. K., Pinelli, M., de Bie, C. I., Mustonen, A., Maatta, T., Arts, H. H., Wu, K., Roepman, R., Moilanen, J. S., Raza, S., Varilo, T., Scala, G., Cocozza, S., Gilissen, C., van Gassen, K. L. I., Jarvela, I. Identification of C12orf4 as a gene for autosomal recessive intellectual disability. Clin. Genet. 91: 100-105, 2017. [PubMed: 27311568, related citations] [Full Text]
Reuter, M. S., Tawamie, H., Buchert, R., Hosney Gebril, O., Froukh, T., Thiel, C., Uebe, S., Ekici, A. B., Krumbiegel, M., Zweier, C., Hoyer, J., Eberlein, K., and 18 others. Diagnostic yield and novel candidate genes by exome sequencing in 152 consanguineous families with neurodevelopmental disorders. JAMA Psychiat. 74: 293-299, 2017. [PubMed: 28097321, related citations] [Full Text]
Alternative titles; symbols
ORPHA: 88616; DO: 0081227;
Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
---|---|---|---|---|---|---|
12p13.32 | Intellectual developmental disorder, autosomal recessive 66 | 618221 | Autosomal recessive | 3 | C12orf4 | 616082 |
A number sign (#) is used with this entry because of evidence that autosomal recessive intellectual developmental disorder-66 (MRT66) is caused by homozygous mutation in the C12ORF4 gene (616082) on chromosome 12p13.
MRT66 is a nonsyndromic autosomal recessive intellectual developmental disorder with delayed speech development, neuropsychiatric symptoms, and relatively normal life span (Philips et al., 2017).
Alazami et al. (2015) reported a 12-year-old boy and his 8-year-old sister, born of first-cousin Saudi Arabian parents, with MRT66. The boy was more than 2 years of age when he walked, and had single-syllable words at 1 year, although his speech was incomprehensible at the age of 12. MRI showed nonspecific foci at high signal intensities scattered in the white matter of both cerebral hemispheres. Six years later, MRI showed interval stable appearance with multiple T2 intensities in the white matter. His sister was similarly affected. Physical exam showed subtle dysmorphic features in the form of epicanthal folds, pointed nasal tip, and exaggerated antihelix. He also had mild hyperlaxity, hypotonia, normal strength and reflexes, 2 hypopigmented patches, and 1 hyperpigmented patch.
Philips et al. (2017) reported 2 Finnish families segregating autosomal recessive mild to severe nonsyndromic intellectual disability with mutation in the C12ORF4 gene. These 2 families were found to have common ancestors in the mid to late 18th century. Five males and 2 females ranging in age from 46 to 65 years were reported. All had delayed speech development, and 1 had gait abnormalities. There were no significant dysmorphic features. The intellectual disability phenotype was milder in females. Philips et al. (2017) also reported a Dutch female from a consanguineous family with a complex insertion/deletion in C12ORF4. When evaluated at age 10 years she had moderate intellectual disability, autism spectrum disorder, and delayed speech development. Mild dysmorphic features including a long philtrum and full lips, as well as hyperlaxity, were present. Her hands were small and her gait was described as stiff and asymmetric. Brain MRI at age 6 years showed slightly increased T2 signal intensity of the cerebral white matter. Philips et al. (2017) also reported the sibs with MRT66 originally reported by Alazami et al. (2015).
Reuter et al. (2017) reported a consanguineous Turkish family (MR114) with 2 affected sibs with MRT66. The only phenotype described was that of moderate intellectual disability.
In affected sibs from a consanguineous Saudi family with an autosomal recessive intellectual developmental disorder, Alazami et al. (2015) detected homozygosity for a 4-basepair insertion in the C12ORF4 gene (616082.0001) resulting in frameshift.
In affected members of 2 distantly related Finnish families with MRT66, Philips et al. (2017) reported a homozygous missense mutation (L328P; 616082.0002) in the C12ORF4 gene. This variant was found at a frequency of 1 in 53 among blood donors from a northeastern subisolate of Finland.
Reuter et al. (2017) reported homozygosity for a nonsense mutation in the C12ORF4 gene (R454X; 616082.0003) in affected members of a consanguineous Turkish family presenting with moderately impaired intellectual development.
Alazami, A. M., Patel, N., Shamseldin, H. E., Anazi, S., Al-Dosari, M. S., Alzahrani, F., Hijazi, H., Alshammari, M., Aldahmesh, M. A., Salih, M. A., Faqeih, E., Alhashem, A., and 41 others. Accelerating novel candidate gene discovery in neurogenetic disorders via whole-exome sequencing of prescreened multiplex consanguineous families. Cell Rep. 10: 148-161, 2015. [PubMed: 25558065] [Full Text: https://doi.org/10.1016/j.celrep.2014.12.015]
Philips, A. K., Pinelli, M., de Bie, C. I., Mustonen, A., Maatta, T., Arts, H. H., Wu, K., Roepman, R., Moilanen, J. S., Raza, S., Varilo, T., Scala, G., Cocozza, S., Gilissen, C., van Gassen, K. L. I., Jarvela, I. Identification of C12orf4 as a gene for autosomal recessive intellectual disability. Clin. Genet. 91: 100-105, 2017. [PubMed: 27311568] [Full Text: https://doi.org/10.1111/cge.12821]
Reuter, M. S., Tawamie, H., Buchert, R., Hosney Gebril, O., Froukh, T., Thiel, C., Uebe, S., Ekici, A. B., Krumbiegel, M., Zweier, C., Hoyer, J., Eberlein, K., and 18 others. Diagnostic yield and novel candidate genes by exome sequencing in 152 consanguineous families with neurodevelopmental disorders. JAMA Psychiat. 74: 293-299, 2017. [PubMed: 28097321] [Full Text: https://doi.org/10.1001/jamapsychiatry.2016.3798]
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