Coffin–Siris syndrome

A genetic chromatin-remodeling disorder caused by mutations in genes of the BAF (SWI/SNF) complex, which regulates gene expression during development.

Genetic basis

Most cases are - De novo autosomal dominant mutations

Major genes involved:

Gene	Frequency	Clinical relevance
ARID1B	Most common (~60–70%)	Milder but classic CSS
SMARCA4	Less common	Often more severe
SMARCB1	Rare	Severe forms
ARID1A	Rare	Multisystem involvement
SMARCE1	Rare	Variable severity

Core defining clinical feature

Hypoplastic or absent fifth fingernails or toenails

Prenatally,

• Small distal phalanx of 5th digit
• Short or absent terminal phalanx
• Abnormal fifth digit morphology

Prenatal ultrasound findings

There is no single pathognomonic sign

A. Central nervous system findings

Common and earliest.

• Agenesis or hypoplasia of corpus callosum

Other CNS findings:

• Ventriculomegaly
• Delayed sulcation
• Cerebellar hypoplasia
• Dandy–Walker spectrum
• Microcephaly

B. Limb abnormalities

Fifth digit abnormalities

• Short fifth finger
• Hypoplastic distal phalanx
• Absent nail
• Brachydactyly

C. Facial abnormalities

• Coarse facial profile
• Depressed nasal bridge
• Thick lips
• Micrognathia

D. Growth abnormalities

• Fetal growth restriction (FGR)
• Small head size
• Reduced long bone growth

E. Cardiac abnormalities

• Ventricular septal defect
• Atrial septal defect
• Outflow tract anomalies

Most suggestive prenatal pattern - ACC + FGR + distal fifth digit abnormality

MRI findings

• Corpus callosum abnormalities
• Delayed cortical development
• Cerebellar abnormalities

Postnatal features

• Developmental delay
• Intellectual disability
• Speech delay
• Feeding difficulty
• Recurrent infections

Long-term outcomes

• Moderate to severe intellectual disability
• Behavioral difficulties
• Delayed motor development

SMARCA4 variant explanation

A heterozygous 3’splice site variant in intron 6 of the SMARCA4 gene (chr19:g.10989315A>T; Depth: 164x) that affects the invariant AG acceptor splice site upstream of exon 7 in a fetus with bilateral club feet

SMARCA4

Key systems affected:

• Brain
• Limbs
• Heart
• Facial development

Coffin–Siris syndrome: Autosomal dominant; One abnormal copy can cause disease.

3′ splice site variant – essential regions that tell the cell how to remove introns.

A 3′ splice site is the acceptor site before an exon.

If this AG is altered

• May skip exon 7
• May insert abnormal sequence
• May create truncated protein

This usually leads to loss-of-function

Loss-of-function in SMARCA4 is well-established pathogenic mechanism.

Because it affects invariant splice acceptor site

Most likely exon skipping (exon 7 lost)

Possible:

• Truncated protein
• Nonsense-mediated decay
• Loss of functional protein

This is high-risk type mutation

Counseling challenge

Difficult part of counseling in SMARCA4 variants with minimal prenatal phenotype:

• Many features of Coffin–Siris syndrome are primarily postnatal
• Especially neurodevelopmental delay and characteristic facial features

So even with a normal fetal scan, uncertainty remains.

A normal prenatal phenotype does not exclude postnatal manifestations.

This is true for many genes involved in chromatin remodeling, including: SMARCA4

Because many features of Coffin–Siris spectrum are:

• Developmental delay
• Speech delay
• Behavioral issues
• Learning disability

These cannot be detected prenatally.

What ultrasound can and cannot predict

Ultrasound can predict:

• Structural severity:
  • Brain malformations
  • Heart defects
  • Limb anomalies
  • Growth restriction

Ultrasound cannot predict:

• Functional outcomes:
  • Cognitive ability
  • Speech development
  • Learning capacity
  • Behavioral profile

So:

Even with normal scans: Neurodevelopmental risk still exists.

With:

• Likely de novo SMARCA4 splice variant
• Isolated bilateral TEV
• No other anomalies

There is a measurable risk of postnatal developmental disorder, but absence of major structural anomalies significantly reduces the likelihood of severe multisystem disease. Outcome remains uncertain and variable.