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Neurogenetics

Coffin-Siris syndrome

Coffin-Siris syndrome is a rare genetic disorder characterised by developmental delay, intellectual disability, and a range of distinctive physical traits. It typically manifests from birth and can vary in severity, impacting individuals differently.

Autosomal dominant Neurogenetics Tier B OMIM:135900
Rare
Prevalence
Population estimate
50%
Inheritance
Autosomal dominant - chance of passing to each child
3
Associated genes
ARID1B, SMARCA4, SMARCB1

Overview

Coffin-Siris syndrome is a rare genetic condition that affects multiple body systems. Individuals with this syndrome often experience developmental delay, ranging from mild to severe, and intellectual disability. Characteristic physical features can also be present, such as underdeveloped or absent nails on the fifth (little) fingers and toes, and coarse facial features. The condition is usually identified in infancy or early childhood due to these developmental and physical signs.

The syndrome was first described in 1970 by Coffin and Siris. While the severity can vary significantly between individuals, early diagnosis and management are important for supporting affected children and their families. It is a lifelong condition, and management focuses on addressing specific symptoms and developmental needs [PMID:33659220].

Symptoms & clinical features

The symptoms of Coffin-Siris syndrome can be quite varied, but developmental delay is a consistent feature, affecting motor skills, speech, and cognitive abilities. Intellectual disability is typically present, ranging from mild learning difficulties to more severe intellectual impairment. Many children with Coffin-Siris syndrome have challenges with speech development, often requiring speech therapy support.

Characteristic physical features are often observed. These can include abnormalities of the fifth digit, such as hypoplastic (underdeveloped) or aplastic (absent) nails and distal phalanges (the outermost bone in the finger or toe) [PMID:24177218]. Facial features may appear distinctive, with thick eyebrows, long eyelashes, a broad nasal bridge, and a wide mouth. Other potential symptoms include microcephaly (a smaller-than-average head circumference), short stature, and feeding difficulties in infancy. Some individuals may also experience congenital heart defects, kidney abnormalities, or seizures [PMID:24177218].

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Affected organs

Coffin-Siris syndrome primarily affects the brain, leading to the observed developmental delay and intellectual disability. Structural brain anomalies, such as abnormalities of the corpus callosum (the bridge connecting the two halves of the brain) or cerebellar hypoplasia (underdevelopment of part of the brain responsible for coordination), may be present in some individuals. The skeletal system can also be affected, most notably with the characteristic changes to the nails and bones of the fifth fingers and toes.

Beyond the neurological and skeletal systems, other organs can occasionally be involved. These may include the heart, with a small percentage of individuals having congenital heart defects, and the kidneys, which can sometimes show structural abnormalities. The eyes and ears can also be impacted, potentially leading to vision or hearing impairment in some cases.

Brain
Brain
Central nervous system involvement
Cellular impact
Cellular impact
Mechanism at cellular level

Risks & severity

Coffin-Siris syndrome is a rare condition, and its exact prevalence is not well established. The severity of the syndrome can vary widely, even among individuals with the same genetic cause. Some individuals may have mild developmental delays and subtle physical features, while others experience more profound intellectual disability and significant health complications. The degree of developmental delay and intellectual disability is a major factor in determining the overall impact on an individual's life.

Complications such as feeding difficulties in infancy, recurrent infections, and seizures can contribute to the severity of the condition and require ongoing medical attention. While the condition is present from birth, the full spectrum of developmental challenges often becomes more apparent as a child grows. There is no typical age of onset for symptoms as they are generally present from infancy, with developmental milestones being missed or delayed.

Genetic causes

Coffin-Siris syndrome is caused by pathogenic variants (genetic changes) in genes that are important for the development and function of many body systems. Several genes have been linked to the condition, including ARID1B, SMARCA4, and SMARCB1 [PMID:24177218]. These genes provide instructions for making proteins that are part of a larger complex called the SWI/SNF complex.

The SWI/SNF complex plays a critical role in gene regulation. It helps to control when and where genes are turned on or off by remodelling chromatin, which is the tightly packed structure of DNA and proteins within cells. By altering how DNA is packaged, the SWI/SNF complex makes genes more or less accessible for transcription, thereby influencing cell growth, division, and differentiation. When there is a pathogenic variant in genes like ARID1B, SMARCA4, or SMARCB1, the SWI/SNF complex may not function correctly, leading to the developmental problems and other features seen in Coffin-Siris syndrome.

  • ARID1B
    AT-rich interaction domain 1B
    The ARID1B gene encodes a protein that is a crucial component of SWI/SNF protein complexes, which regulate gene expression through chromatin remodelling and are implicated in various developmental processes.
  • SMARCA4
    SWI/SNF related BAF chromatin remodeling complex subunit ATPase 4
  • SMARCB1
    SWI/SNF related BAF chromatin remodeling complex subunit B1

Inheritance pattern

Coffin-Siris syndrome is typically inherited in an autosomal dominant pattern. This means that a person only needs one copy of an altered gene in each cell to develop the condition. In most cases of Coffin-Siris syndrome, the pathogenic variant occurs spontaneously (de novo) in the affected individual and is not inherited from either parent. This means that neither parent carries the genetic change.

If Coffin-Siris syndrome is caused by a de novo variant, the chance of future children in the same family being affected is generally very low. However, if a parent is found to have the genetic variant, even if they show no or very mild symptoms, there is a 50% chance with each pregnancy that their child will inherit the variant. Genetic counselling can provide detailed information about inheritance patterns and recurrence risks for families.

♀ Affected parent 1 altered copy ♂ Unaffected parent 2 typical copies Affected Unaffected Unaffected Affected Affected Carrier Unaffected Circles = females · Squares = males

Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.

Diagnosis & testing

The diagnosis of Coffin-Siris syndrome is usually suspected based on the characteristic clinical features observed in an individual, such as developmental delay, intellectual disability, and distinctive physical traits. However, because these features can overlap with other genetic conditions, a definitive diagnosis requires genetic testing.

Genetic testing typically involves analysing DNA to identify pathogenic variants in genes known to be associated with Coffin-Siris syndrome, such as ARID1B, SMARCA4, and SMARCB1. This can be done through a gene panel that looks at multiple relevant genes or more comprehensive tests like whole exome sequencing. In the UK, genetic testing for suspected Coffin-Siris syndrome would typically be requested by a clinical geneticist or paediatrician and fall under the NHS Genomic Medicine Service, often utilising specific R-codes for developmental disorders and intellectual disability panels.

Management & lifestyle

There is no cure for Coffin-Siris syndrome, so management focuses on addressing the specific symptoms and supporting the developmental needs of each individual. A multidisciplinary team approach is often recommended, involving paediatricians, neurologists, geneticists, and various therapists.

Early intervention therapies are crucial, including physiotherapy to help with motor skills, occupational therapy for daily living activities, and speech and language therapy to support communication development. Educational support tailored to the individual's learning needs is also essential. Regular medical monitoring for potential complications, such as cardiac or renal issues, may be part of the care plan. Genetic counsellors can also provide valuable support and information to families regarding the condition and its implications.

UK care pathway

In the UK, individuals suspected of having a rare genetic condition like Coffin-Siris syndrome would typically be referred by their GP or a specialist paediatrician to a Clinical Genetics service within the NHS. Genetic counselling is an integral part of this pathway, providing families with information, support, and guidance through the diagnostic process and beyond. Genetic testing, often under specific R-codes within the NHS Genomic Medicine Service, would then be undertaken to identify the causative genetic variant. The outcomes of these tests are crucial for confirming a diagnosis and informing ongoing management plans, which are then coordinated by paediatricians and other relevant specialists.

Frequently asked questions

Is Coffin-Siris syndrome always inherited from parents?

No, in most cases, Coffin-Siris syndrome is caused by a new genetic change (de novo variant) that happens for the first time in the affected individual and is not inherited from their parents. In rare instances, it can be inherited if a parent also carries the genetic change.

What kind of support is available for children with Coffin-Siris syndrome?

Children with Coffin-Siris syndrome benefit from a range of support services. This often includes early intervention therapies such as physiotherapy, occupational therapy, and speech and language therapy, as well as educational support tailored to their individual learning needs. A multidisciplinary team of healthcare professionals typically coordinates this care.

Will a person with Coffin-Siris syndrome have a normal life expectancy?

While Coffin-Siris syndrome is a lifelong condition, life expectancy can vary depending on the severity of symptoms and the presence of any associated health complications, such as significant heart defects or severe feeding issues. Many individuals can live into adulthood, with ongoing medical and developmental support.

How rare is Coffin-Siris syndrome?

Coffin-Siris syndrome is considered a very rare genetic condition. The exact number of affected individuals is not precisely known, but it is one of many conditions classified as 'ultra-rare'.

Can Coffin-Siris syndrome be diagnosed before birth?

Prenatal diagnosis is possible if a specific genetic variant has already been identified in a family member. However, for most families where the condition arises spontaneously (de novo), it is typically diagnosed after birth based on clinical features and confirmed by genetic testing.

References

  1. Curcio MR, Ferranti S, Lotti F. Coffin-Siris syndrome and epilepsy. Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology. 2021. PMID: 33006724
  2. Adam MP, Bick S, Mirzaa GM. Coffin-Siris Syndrome. 1993. PMID: 23556151
  3. Vasko A, Drivas TG, Schrier Vergano SA. Genotype-Phenotype Correlations in 208 Individuals with Coffin-Siris Syndrome. Genes. 2021. PMID: 34205270
  4. Borja NA, Schrier Vergano SA, Tekin M. Coffin-Siris syndrome and cancer susceptibility. Genetics in medicine open. 2023. PMID: 39669229
  5. Adam MP, Bick S, Mirzaa GM. ARID1B-Related Disorder. 1993. PMID: 31132234
  6. Levy P, Baraitser M. Coffin-Siris syndrome. Journal of medical genetics. 1991. PMID: 1865473
  7. van der Sluijs PJ, Jansen S, Vergano SA. The ARID1B spectrum in 143 patients: from nonsyndromic intellectual disability to Coffin-Siris syndrome. Genetics in medicine : official journal of the American College of Medical Genetics. 2019. PMID: 30349098
  8. Mardinian K, Adashek JJ, Botta GP. SMARCA4: Implications of an Altered Chromatin-Remodeling Gene for Cancer Development and Therapy. Molecular cancer therapeutics. 2021. PMID: 34642211
Educational content. This page is not medical or genetic advice, is not individually reviewed by a clinician for each reader, and should not replace a consultation with a qualified healthcare professional or genetic counsellor.