Coffin-Siris Syndrome 2

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.

Description

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.

Clinical Features

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.

Molecular Genetics

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.