#618362
Table of Contents
| Location | Phenotype | Inheritance |
Phenotype mapping key |
Phenotype MIM number |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 1p36.11 | Coffin-Siris syndrome 2 | AD | 3 | 614607 | ARID1A | 603024 |
| 2p25.2 | Intellectual developmental disorder with microcephaly and with or without ocular malformations or hypogonadotropic hypogonadism | AD | 3 | 615866 | SOX11 | 600898 |
| 6p22.3 | Coffin-Siris syndrome 10 | AD | 3 | 618506 | SOX4 | 184430 |
| 6q25.3 | Coffin-Siris syndrome 1 | AD | 3 | 135900 | ARID1B | 614556 |
| 11q13.1 | Coffin-Siris syndrome 7 | AD | 3 | 618027 | DPF2 | 601671 |
| 12q12 | Coffin-Siris syndrome 6 | AD | 3 | 617808 | ARID2 | 609539 |
| 12q13.12 | Coffin-Siris syndrome 11 | AD | 3 | 618779 | SMARCD1 | 601735 |
| 12q13.2 | Coffin-Siris syndrome 8 | AD | 3 | 618362 | SMARCC2 | 601734 |
| 17q21.2 | Coffin-Siris syndrome 5 | AD | 3 | 616938 | SMARCE1 | 603111 |
| 19p13.2 | Coffin-Siris syndrome 4 | AD | 3 | 614609 | SMARCA4 | 603254 |
| 19q13.33 | Coffin-Siris syndrome 12 | AD | 3 | 619325 | BICRA | 605690 |
| 22q11.23 | Coffin-Siris syndrome 3 | AD | 3 | 614608 | SMARCB1 | 601607 |
A number sign (#) is used with this entry because of evidence that Coffin-Siris syndrome-8 (CSS8) is caused by heterozygous mutation in the SMARCC2 gene (601734) on chromosome 12q13.
Coffin-Siris syndrome-8 (CSS8) is characterized by variable degrees of impaired intellectual development including speech impairment, hypotonia, feeding difficulties, and behavioral abnormalities. Dysmorphic features may or may not be present and include hypertrichosis or thin scalp hair, thick eyebrows, thin upper vermilion, and upturned nose (Machol et al., 2019).
For a general phenotypic description and a discussion of genetic heterogeneity of Coffin-Siris syndrome, see CSS1 (135900).
As part of a study of 119 patients with undiagnosed genetic disorders analyzed by whole-exome sequencing, Zhu et al. (2015) identified a 7-year-old boy with failure to thrive, benign hydrocephalus, speech delay, hypotonia, elevated lactate and ammonia, vitiligo, and developmental delay. Seizures and regression were absent.
Martinez et al. (2017) identified a girl with impaired intellectual development, delayed speech and language development, hypotonia, short stature, abnormalities of the mouth and nose, skeletal abnormalities, hypertrichosis and synophrys, sleep disturbances, and seizures.
Machol et al. (2019) studied 15 unrelated individuals with impaired intellectual development with speech and behavioral abnormalities, hypotonia, and varying dysmorphism. Two of these individuals had been reported by Zhu et al. (2015) and Martinez et al. (2017), respectively. Eight individuals had absent speech, and a total of 13 of the 15 had some speech abnormalities. Ten had behavioral problems including aggression, self-injurious behavior, hyperactivity, hypersensitivity to touch, sleep disturbances, and obsessive or rigid behavior. Six of the 15 had failure to thrive, and 8 had sucking or feeding difficulties. Thirteen had hypotonia, 2 manifested spasticity, 4 had seizures, and 2 had a movement disorder. Six of the 12 patients who had brain MRIs had abnormalities which included white matter lesions, white matter loss, thinning of the corpus callosum, generalized cerebral atrophy, and hypomyelination. Four had fifth finger or toenail anomalies. Five had scoliosis, with 1 of those manifesting as kyphosis. Only 2 had cardiovascular abnormalities. While a typical facial gestalt was not observed, 11 of the 15 were reported to have dysmorphic craniofacial features, the most pronounced of which were hypertrichosis, thick eyebrows/prominent supraorbital ridges, thin upper or thick lower lip vermilion, and upturned nose/anteverted nostrils.
The transmission pattern of CSS8 in the families reported by Machol et al. (2019) was consistent with autosomal dominant inheritance.
In 15 patients with Coffin-Siris syndrome, Machol et al. (2019) detected 13 heterozygous mutations in the SMARCC2 gene, 12 of which were shown to have occurred de novo. Three mutations affected splicing, 1 resulted in frameshift, 1 caused a premature termination codon, 7 were missense, and 1 was an in-frame single amino acid deletion. Two mutations were recurrent. All 7 missense mutations occurred in highly conserved amino acids and were predicted to be deleterious by various in silico tools. The mutations clustered in the SWIRM and SANT domains of the protein, and the majority of missense and splice site mutations suggested a dominant-negative mechanism.
Machol, K., Rousseau, J., Ehresmann, S., Garcia, T., Nguyen, T. T. M., Spillmann, R. C., Sullivan, J. A., Shashi, V., Jiang, Y., Stong, N., Fiala, E., Willing, M., and 34 others. Expanding the spectrum of BAF-related disorders: de novo variants in SMARCC2 cause a syndrome with intellectual disability and developmental delay. Am. J. Hum. Genet. 104: 164-178, 2019. [PubMed: 30580808, images, related citations] [Full Text]
Martinez, F., Caro-Llopis, A., Rosello, M., Oltra, S., Mayo, S., Monfort, S., Orellana, C. High diagnostic yield of syndromic intellectual disability by targeted next-generation sequencing. J. Med. Genet. 54: 87-92, 2017. [PubMed: 27620904, related citations] [Full Text]
Zhu, X., Petrovski, S., Xie, P., Ruzzo, E. K., Lu, Y.-F., McSweeney, K. M., Ben-Zeev, B., Nissenkorn, A., Anikster, Y., Oz-Levi, D., Dhindsa, R. S., Hitomi, Y., and 15 others. Whole-exome sequencing in undiagnosed genetic diseases: interpreting 119 trios. Genet. Med. 17: 774-781, 2015. [PubMed: 25590979, related citations] [Full Text]
ORPHA: 1465; DO: 0112367;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 12q13.2 | Coffin-Siris syndrome 8 | 618362 | Autosomal dominant | 3 | SMARCC2 | 601734 |
A number sign (#) is used with this entry because of evidence that Coffin-Siris syndrome-8 (CSS8) is caused by heterozygous mutation in the SMARCC2 gene (601734) on chromosome 12q13.
Coffin-Siris syndrome-8 (CSS8) is characterized by variable degrees of impaired intellectual development including speech impairment, hypotonia, feeding difficulties, and behavioral abnormalities. Dysmorphic features may or may not be present and include hypertrichosis or thin scalp hair, thick eyebrows, thin upper vermilion, and upturned nose (Machol et al., 2019).
For a general phenotypic description and a discussion of genetic heterogeneity of Coffin-Siris syndrome, see CSS1 (135900).
As part of a study of 119 patients with undiagnosed genetic disorders analyzed by whole-exome sequencing, Zhu et al. (2015) identified a 7-year-old boy with failure to thrive, benign hydrocephalus, speech delay, hypotonia, elevated lactate and ammonia, vitiligo, and developmental delay. Seizures and regression were absent.
Martinez et al. (2017) identified a girl with impaired intellectual development, delayed speech and language development, hypotonia, short stature, abnormalities of the mouth and nose, skeletal abnormalities, hypertrichosis and synophrys, sleep disturbances, and seizures.
Machol et al. (2019) studied 15 unrelated individuals with impaired intellectual development with speech and behavioral abnormalities, hypotonia, and varying dysmorphism. Two of these individuals had been reported by Zhu et al. (2015) and Martinez et al. (2017), respectively. Eight individuals had absent speech, and a total of 13 of the 15 had some speech abnormalities. Ten had behavioral problems including aggression, self-injurious behavior, hyperactivity, hypersensitivity to touch, sleep disturbances, and obsessive or rigid behavior. Six of the 15 had failure to thrive, and 8 had sucking or feeding difficulties. Thirteen had hypotonia, 2 manifested spasticity, 4 had seizures, and 2 had a movement disorder. Six of the 12 patients who had brain MRIs had abnormalities which included white matter lesions, white matter loss, thinning of the corpus callosum, generalized cerebral atrophy, and hypomyelination. Four had fifth finger or toenail anomalies. Five had scoliosis, with 1 of those manifesting as kyphosis. Only 2 had cardiovascular abnormalities. While a typical facial gestalt was not observed, 11 of the 15 were reported to have dysmorphic craniofacial features, the most pronounced of which were hypertrichosis, thick eyebrows/prominent supraorbital ridges, thin upper or thick lower lip vermilion, and upturned nose/anteverted nostrils.
The transmission pattern of CSS8 in the families reported by Machol et al. (2019) was consistent with autosomal dominant inheritance.
In 15 patients with Coffin-Siris syndrome, Machol et al. (2019) detected 13 heterozygous mutations in the SMARCC2 gene, 12 of which were shown to have occurred de novo. Three mutations affected splicing, 1 resulted in frameshift, 1 caused a premature termination codon, 7 were missense, and 1 was an in-frame single amino acid deletion. Two mutations were recurrent. All 7 missense mutations occurred in highly conserved amino acids and were predicted to be deleterious by various in silico tools. The mutations clustered in the SWIRM and SANT domains of the protein, and the majority of missense and splice site mutations suggested a dominant-negative mechanism.
Machol, K., Rousseau, J., Ehresmann, S., Garcia, T., Nguyen, T. T. M., Spillmann, R. C., Sullivan, J. A., Shashi, V., Jiang, Y., Stong, N., Fiala, E., Willing, M., and 34 others. Expanding the spectrum of BAF-related disorders: de novo variants in SMARCC2 cause a syndrome with intellectual disability and developmental delay. Am. J. Hum. Genet. 104: 164-178, 2019. [PubMed: 30580808] [Full Text: https://doi.org/10.1016/j.ajhg.2018.11.007]
Martinez, F., Caro-Llopis, A., Rosello, M., Oltra, S., Mayo, S., Monfort, S., Orellana, C. High diagnostic yield of syndromic intellectual disability by targeted next-generation sequencing. J. Med. Genet. 54: 87-92, 2017. [PubMed: 27620904] [Full Text: https://doi.org/10.1136/jmedgenet-2016-103964]
Zhu, X., Petrovski, S., Xie, P., Ruzzo, E. K., Lu, Y.-F., McSweeney, K. M., Ben-Zeev, B., Nissenkorn, A., Anikster, Y., Oz-Levi, D., Dhindsa, R. S., Hitomi, Y., and 15 others. Whole-exome sequencing in undiagnosed genetic diseases: interpreting 119 trios. Genet. Med. 17: 774-781, 2015. [PubMed: 25590979] [Full Text: https://doi.org/10.1038/gim.2014.191]
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