#614607
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-2 (CSS2) is caused by heterozygous mutation in the ARID1A gene (603024) on chromosome 1p36.
Coffin-Siris syndrome is a congenital malformation syndrome characterized by developmental delay, intellectual disability, coarse facial features, feeding difficulties, and hypoplastic or absent fifth fingernails and fifth distal phalanges. Other more variable features may also occur. Patients with ARID1A mutations have a wide spectrum of manifestations, from severe intellectual disability and serious internal complications that could result in early death to mild intellectual disability (summary by Kosho et al., 2014).
For a general phenotypic description and a discussion of genetic heterogeneity of Coffin-Siris syndrome, see CSS1 (135900).
The chromosome 1p36.11 duplication syndrome, in which the ARID1A gene is duplicated, is characterized by impaired intellectual development, microcephaly, dysmorphic facial features, and hand and foot anomalies.
Tsurusaki et al. (2012) reported 3 individuals with developmental delay, abnormal corpus callosum, absent/hypoplastic fifth finger/toenails, sparse scalp hair, long eyelashes, and a coarse facial appearance with wide mouth, thick lips, and abnormal ears. Seizures, ptosis, and macroglossia were not reported. All had feeding and sucking problems as well as frequent infections and cardiac findings. Two of 3 examined had short stature, and 2 of 2 examined had absent/hypoplastic fifth phalanx of hands and feet.
Wieczorek et al. (2013) reported a boy with CSS2. He had low frontal hairline, thick and arched eyebrows, long eyelashes, ptosis, low-set ears, thin upper and full lower vermilion borders, flat nasal bridge, broad nose, large mouth, macroglossia, and abnormal ears. Skeletal findings included brachytelephalangy with mild nail hypoplasia of all fingers and toes as well as prominent interphalangeal joints and delayed bone age. He had delayed psychomotor development with hypotonia and seizures; brain imaging showed abnormal corpus callosum.
Santen et al. (2013) reported 4 unrelated patients with CSS2. Clinical features included hypotonia, feeding problems, vision problems, delayed psychomotor development with poor speech, and dysmorphic facial features, including thick eyebrows, long eyelashes, flat nasal bridge, thick alae nasi, anteverted nose, thick lower vermilion, and malformed ears. Patients had general brachydactyly with hypoplastic nails and delayed dentition. Brain imaging showed agenesis of the corpus callosum in 2 patients.
Chromosome 1p36.11 Microduplication Syndrome
Bidart et al. (2017) reported 4 patients with similar microduplications on chromosome 1p36.11 involving the ARID1A gene. Patient 1 had originally been reported by Coutton et al. (2013). The patients shared a similar phenotype consisting primarily of microcephaly, impaired intellectual development, delayed motor milestones, hand and foot anomalies, growth impairment, constipation, frequent airway infections, dysmorphic facial features, and stereotypies. All patients had a characteristic nasal tip with notched alae nasi and a low columella. Deficiency of the lateral vermilion border of the upper lip was also seen, as well as a high forehead and sparse hair. The feet were very distinctive, with brachydactyly and shortening and medial deviation of the great toes. Two genes, ARID1A and PIGV, were included in the minimal critical region; the ARID1A gene was fully duplicated, whereas the PIGV gene was partially included. Two of the patients were hypotonic, 3 had stereotypical behaviors, and none had seizures. Age at the time of the report ranged from 6 to 34 years.
In 3 patients with Coffin-Siris syndrome, Tsurusaki et al. (2012) identified mutations in the ARID1A gene: a frameshift (603024.0001) and 2 premature termination mutations (603024.0002, 603024.0003). The patient with the frameshift mutation presented with hepatoblastoma. Haploinsufficiency and/or homozygous inactivation of ARID1A have been found in several types of cancer, but not in hepatoblastoma.
Using a combination of whole-exome sequencing, next-generation sequencing of 23 SWI/SNF complex genes, and molecular karyotyping, Wieczorek et al. (2013) identified mutations in 28 (60%) of 46 patients with a clinical phenotype consistent with Coffin-Siris syndrome or Nicolaides-Baraitser syndrome (NCBRS; 601358), which shows similar features. Only 1 patient had a heterozygous truncating mutation in the ARID1A gene, which was likely somatic mosaic (R1989X; 603024.0004). Functional studies of the variant were not performed.
In 4 unrelated patients with CSS2, Santen et al. (2013) identified 4 different de novo heterozygous pathogenic mutations in the ARID1A gene (see, e.g., 603024.0005-603024.0006). The mutations were all shown to be somatic mosaic, although to different extents. Santen et al. (2013) noted that homozygous loss of the Arid1a gene is embryonic lethal in mice, and suggested that truncating germline variants in the ARID1A gene may be embryonic lethal in humans as well. The patients were ascertained from a large cohort of 63 patients with a clinical diagnosis of CSS who were screened for mutations in the 6 genes of the BAF complex. Functional studies of the variants were not performed.
Chromosome 1p36.11 Microduplication
The chromosome 1p36.11 microduplications in the 4 patients with syndromic impaired intellectual development reported by Bidart et al. (2017) ranged from 190 to 327 kb. The minimal critical region for the duplication was 122 kb (chr1:27,001,256-27,123,236, GRCh37) and included in every case full duplication of the ARID1A gene and partial duplication of the PIGV (610274) gene. These were the only 2 genes involved in the duplication. RNA-seq and quantitative RT-PCR demonstrated a 1.5-fold overexpression of ARID1A in patients, whereas PIGV expression was not altered. Transcriptomic analysis revealed the deregulated expression of several genes involved in microcephaly and developmental disorders as well as the involvement of signaling pathways relevant to microcephaly, including the polo-like kinase (PLK) pathway (see PLK1, 602098). RNA-seq analysis showed deregulation of genes involved in cell cycle, cell proliferation, cell death, and DNA replication, recombination, and repair for which ARID1A had been demonstrated to be a key transcriptional regulator. Bidart et al. (2017) also noted that no duplications that fully include ARID1A had been reported in any databases of copy number variation from healthy subjects.
Bidart, M., El Atifi, M., Miladi, S., Rendu, J., Satre, V., Ray, P. F., Bosson, C., Devillard, F., Lehalle, D., Malan, V., Amiel, J., Mencarelli, M. A., and 9 others. Microduplication of the ARID1A gene causes intellectual disability with recognizable syndromic features. Genet. Med. 19: 701-710, 2017. [PubMed: 27906199, related citations] [Full Text]
Coutton, C., Bidart, M., Rendu, J., Devillard, F., Vieville, G., Amblard, F., Lopez, G., Jouk, P. S., Satre, V. 190-kb duplication in 1p36.11 including PIGV and ARID1A genes in a girl with intellectual disability and hexadactyly. Clin. Genet. 84: 596-599, 2013. [PubMed: 23521658, related citations] [Full Text]
Kosho, T., Okamoto, N., Coffin-Siris Syndrome International Collaborators. Genotype-phenotype correlation of Coffin-Siris syndrome caused by mutations in SMARCB1, SMARCA4, SMARCE1, and ARID1A. Am. J. Med. Genet. 166C: 262-275, 2014. [PubMed: 25168959, related citations] [Full Text]
Santen, G. W. E., Aten, E., Vulto-van Silfhout, A. T., Pottinger, C., van Bon, B. W. M., van Minderhout, I. J. H. M., Snowdowne, R., van der Lans, C. A. C., Boogaard, M., Linssen, M. M. L., Vijfhuizen, L., van der Wielen, M. J. R., and 11 others. Coffin-Siris syndrome and the BAF complex: genotype-phenotype study in 63 patients. Hum. Mutat. 34: 1519-1528, 2013. [PubMed: 23929686, related citations] [Full Text]
Tsurusaki, Y., Okamoto, N., Ohashi, H., Kosho, T., Imai, Y., Hibi-Ko, Y., Kaname, T., Naritomi, K., Kawame, H., Wakui, K., Fukushima, Y., Homma, T., and 19 others. Mutations affecting components of the SWI/SNF complex cause Coffin-Siris syndrome. Nature Genet. 44: 376-378, 2012. [PubMed: 22426308, related citations] [Full Text]
Wieczorek, D., Bogershausen, N., Beleggia, F., Steiner-Haldenstatt, S., Pohl, E., Li, Y., Milz, E., Martin, M., Thiele, H., Altmuller, J., Alanay, Y., Kayserili, H., and 44 others. A comprehensive molecular study on Coffin-Siris and Nicolaides-Baraitser syndromes identifies a broad molecular and clinical spectrum converging on altered chromatin remodeling. Hum. Molec. Genet. 22: 5121-5135, 2013. [PubMed: 23906836, related citations] [Full Text]
Alternative titles; symbols
Other entities represented in this entry:
ORPHA: 1465; DO: 0070044;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 1p36.11 | Coffin-Siris syndrome 2 | 614607 | Autosomal dominant | 3 | ARID1A | 603024 |
A number sign (#) is used with this entry because of evidence that Coffin-Siris syndrome-2 (CSS2) is caused by heterozygous mutation in the ARID1A gene (603024) on chromosome 1p36.
Coffin-Siris syndrome is a congenital malformation syndrome characterized by developmental delay, intellectual disability, coarse facial features, feeding difficulties, and hypoplastic or absent fifth fingernails and fifth distal phalanges. Other more variable features may also occur. Patients with ARID1A mutations have a wide spectrum of manifestations, from severe intellectual disability and serious internal complications that could result in early death to mild intellectual disability (summary by Kosho et al., 2014).
For a general phenotypic description and a discussion of genetic heterogeneity of Coffin-Siris syndrome, see CSS1 (135900).
The chromosome 1p36.11 duplication syndrome, in which the ARID1A gene is duplicated, is characterized by impaired intellectual development, microcephaly, dysmorphic facial features, and hand and foot anomalies.
Tsurusaki et al. (2012) reported 3 individuals with developmental delay, abnormal corpus callosum, absent/hypoplastic fifth finger/toenails, sparse scalp hair, long eyelashes, and a coarse facial appearance with wide mouth, thick lips, and abnormal ears. Seizures, ptosis, and macroglossia were not reported. All had feeding and sucking problems as well as frequent infections and cardiac findings. Two of 3 examined had short stature, and 2 of 2 examined had absent/hypoplastic fifth phalanx of hands and feet.
Wieczorek et al. (2013) reported a boy with CSS2. He had low frontal hairline, thick and arched eyebrows, long eyelashes, ptosis, low-set ears, thin upper and full lower vermilion borders, flat nasal bridge, broad nose, large mouth, macroglossia, and abnormal ears. Skeletal findings included brachytelephalangy with mild nail hypoplasia of all fingers and toes as well as prominent interphalangeal joints and delayed bone age. He had delayed psychomotor development with hypotonia and seizures; brain imaging showed abnormal corpus callosum.
Santen et al. (2013) reported 4 unrelated patients with CSS2. Clinical features included hypotonia, feeding problems, vision problems, delayed psychomotor development with poor speech, and dysmorphic facial features, including thick eyebrows, long eyelashes, flat nasal bridge, thick alae nasi, anteverted nose, thick lower vermilion, and malformed ears. Patients had general brachydactyly with hypoplastic nails and delayed dentition. Brain imaging showed agenesis of the corpus callosum in 2 patients.
Chromosome 1p36.11 Microduplication Syndrome
Bidart et al. (2017) reported 4 patients with similar microduplications on chromosome 1p36.11 involving the ARID1A gene. Patient 1 had originally been reported by Coutton et al. (2013). The patients shared a similar phenotype consisting primarily of microcephaly, impaired intellectual development, delayed motor milestones, hand and foot anomalies, growth impairment, constipation, frequent airway infections, dysmorphic facial features, and stereotypies. All patients had a characteristic nasal tip with notched alae nasi and a low columella. Deficiency of the lateral vermilion border of the upper lip was also seen, as well as a high forehead and sparse hair. The feet were very distinctive, with brachydactyly and shortening and medial deviation of the great toes. Two genes, ARID1A and PIGV, were included in the minimal critical region; the ARID1A gene was fully duplicated, whereas the PIGV gene was partially included. Two of the patients were hypotonic, 3 had stereotypical behaviors, and none had seizures. Age at the time of the report ranged from 6 to 34 years.
In 3 patients with Coffin-Siris syndrome, Tsurusaki et al. (2012) identified mutations in the ARID1A gene: a frameshift (603024.0001) and 2 premature termination mutations (603024.0002, 603024.0003). The patient with the frameshift mutation presented with hepatoblastoma. Haploinsufficiency and/or homozygous inactivation of ARID1A have been found in several types of cancer, but not in hepatoblastoma.
Using a combination of whole-exome sequencing, next-generation sequencing of 23 SWI/SNF complex genes, and molecular karyotyping, Wieczorek et al. (2013) identified mutations in 28 (60%) of 46 patients with a clinical phenotype consistent with Coffin-Siris syndrome or Nicolaides-Baraitser syndrome (NCBRS; 601358), which shows similar features. Only 1 patient had a heterozygous truncating mutation in the ARID1A gene, which was likely somatic mosaic (R1989X; 603024.0004). Functional studies of the variant were not performed.
In 4 unrelated patients with CSS2, Santen et al. (2013) identified 4 different de novo heterozygous pathogenic mutations in the ARID1A gene (see, e.g., 603024.0005-603024.0006). The mutations were all shown to be somatic mosaic, although to different extents. Santen et al. (2013) noted that homozygous loss of the Arid1a gene is embryonic lethal in mice, and suggested that truncating germline variants in the ARID1A gene may be embryonic lethal in humans as well. The patients were ascertained from a large cohort of 63 patients with a clinical diagnosis of CSS who were screened for mutations in the 6 genes of the BAF complex. Functional studies of the variants were not performed.
Chromosome 1p36.11 Microduplication
The chromosome 1p36.11 microduplications in the 4 patients with syndromic impaired intellectual development reported by Bidart et al. (2017) ranged from 190 to 327 kb. The minimal critical region for the duplication was 122 kb (chr1:27,001,256-27,123,236, GRCh37) and included in every case full duplication of the ARID1A gene and partial duplication of the PIGV (610274) gene. These were the only 2 genes involved in the duplication. RNA-seq and quantitative RT-PCR demonstrated a 1.5-fold overexpression of ARID1A in patients, whereas PIGV expression was not altered. Transcriptomic analysis revealed the deregulated expression of several genes involved in microcephaly and developmental disorders as well as the involvement of signaling pathways relevant to microcephaly, including the polo-like kinase (PLK) pathway (see PLK1, 602098). RNA-seq analysis showed deregulation of genes involved in cell cycle, cell proliferation, cell death, and DNA replication, recombination, and repair for which ARID1A had been demonstrated to be a key transcriptional regulator. Bidart et al. (2017) also noted that no duplications that fully include ARID1A had been reported in any databases of copy number variation from healthy subjects.
Bidart, M., El Atifi, M., Miladi, S., Rendu, J., Satre, V., Ray, P. F., Bosson, C., Devillard, F., Lehalle, D., Malan, V., Amiel, J., Mencarelli, M. A., and 9 others. Microduplication of the ARID1A gene causes intellectual disability with recognizable syndromic features. Genet. Med. 19: 701-710, 2017. [PubMed: 27906199] [Full Text: https://doi.org/10.1038/gim.2016.180]
Coutton, C., Bidart, M., Rendu, J., Devillard, F., Vieville, G., Amblard, F., Lopez, G., Jouk, P. S., Satre, V. 190-kb duplication in 1p36.11 including PIGV and ARID1A genes in a girl with intellectual disability and hexadactyly. Clin. Genet. 84: 596-599, 2013. [PubMed: 23521658] [Full Text: https://doi.org/10.1111/cge.12113]
Kosho, T., Okamoto, N., Coffin-Siris Syndrome International Collaborators. Genotype-phenotype correlation of Coffin-Siris syndrome caused by mutations in SMARCB1, SMARCA4, SMARCE1, and ARID1A. Am. J. Med. Genet. 166C: 262-275, 2014. [PubMed: 25168959] [Full Text: https://doi.org/10.1002/ajmg.c.31407]
Santen, G. W. E., Aten, E., Vulto-van Silfhout, A. T., Pottinger, C., van Bon, B. W. M., van Minderhout, I. J. H. M., Snowdowne, R., van der Lans, C. A. C., Boogaard, M., Linssen, M. M. L., Vijfhuizen, L., van der Wielen, M. J. R., and 11 others. Coffin-Siris syndrome and the BAF complex: genotype-phenotype study in 63 patients. Hum. Mutat. 34: 1519-1528, 2013. [PubMed: 23929686] [Full Text: https://doi.org/10.1002/humu.22394]
Tsurusaki, Y., Okamoto, N., Ohashi, H., Kosho, T., Imai, Y., Hibi-Ko, Y., Kaname, T., Naritomi, K., Kawame, H., Wakui, K., Fukushima, Y., Homma, T., and 19 others. Mutations affecting components of the SWI/SNF complex cause Coffin-Siris syndrome. Nature Genet. 44: 376-378, 2012. [PubMed: 22426308] [Full Text: https://doi.org/10.1038/ng.2219]
Wieczorek, D., Bogershausen, N., Beleggia, F., Steiner-Haldenstatt, S., Pohl, E., Li, Y., Milz, E., Martin, M., Thiele, H., Altmuller, J., Alanay, Y., Kayserili, H., and 44 others. A comprehensive molecular study on Coffin-Siris and Nicolaides-Baraitser syndromes identifies a broad molecular and clinical spectrum converging on altered chromatin remodeling. Hum. Molec. Genet. 22: 5121-5135, 2013. [PubMed: 23906836] [Full Text: https://doi.org/10.1093/hmg/ddt366]
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