Epigenotype-phenotype correlations in Silver-Russell syndrome

Area of Science:

• Genetics
• Pediatrics
• Endocrinology

Background:

• Silver-Russell syndrome (SRS) presents with intrauterine growth restriction, postnatal growth failure, relative macrocephaly, a triangular face, and asymmetry.
• Molecular causes include maternal uniparental disomy of chromosome 7 (mUPD7) in 5-10% and imprinting control region 1 (ICR1) hypomethylation in up to 60% of patients.
• The non-specific nature of SRS features complicates diagnosis, highlighting the need for studies on molecularly confirmed cases.

Purpose of the Study:

• To investigate and compare the clinical phenotypes associated with mUPD7 and ICR1 hypomethylation in Silver-Russell syndrome.
• To identify distinct clinical markers that may aid in differentiating between these two molecular subgroups of SRS.
• To provide valuable clinical information for the diagnosis and management of SRS patients with confirmed molecular diagnoses.

Main Methods:

• A prospective study was conducted on 64 patients diagnosed with SRS.
• Patients were categorized into two molecular subgroups: mUPD7 (n=20) and ICR1 hypomethylation (n=44).
• Detailed clinical data was collected and analyzed to identify differences between the two groups.

Main Results:

• Significant overlap in clinical features between mUPD7 and ICR1 hypomethylation subgroups was observed, making reliable distinction difficult.
• ICR1 hypomethylation was more frequently associated with 'classical' SRS features, asymmetry, fifth finger clinodactyly, and congenital anomalies.
• Learning difficulties and speech therapy referrals were more common in the mUPD7 group, which also showed a higher incidence of mild movement disorders.
• No correlation was found between clinical severity and the level of ICR1 hypomethylation.

Conclusions:

• The clinical overlap between mUPD7 and ICR1 hypomethylation necessitates a low threshold for molecular investigation in suspected SRS cases.
• Distinct clinical features, such as asymmetry and congenital anomalies for ICR1 hypomethylation, and learning difficulties for mUPD7, can aid in subgroup identification.
• Assisted reproductive technology use appears increased in ICR1 hypomethylation cases, and while recurrence risk is generally low, affected siblings were observed.