Isolated Lateralized Overgrowth - Phenotypic Spectrum and Molecular Alterations

Area of Science:

• Genetics
• Developmental Biology
• Endocrinology

Background:

• Isolated Lateralized Overgrowth (ILO) presents diagnostic challenges, often overlapping with conditions like Beckwith-Wiedemann Syndrome (BWS) and Silver-Russell Syndrome (SRS).
• Understanding the molecular basis of ILO is crucial for accurate diagnosis and management.

Purpose of the Study:

• To investigate molecular aberrations at the 11p15.5 locus in patients with ILO.
• To correlate genetic findings with clinical presentation.

Main Methods:

• Methylation-sensitive multiplex ligation-dependent probe amplification (MS-MLPA) was performed on 32 ILO patients.
• Short tandem repeat (STR) marker analysis was used to detect uniparental disomy (UPD).
• Cyclin-dependent kinase inhibitor 1C (CDKN1C) gene sequencing and whole exome sequencing (WES) were conducted when MS-MLPA results were normal.

Main Results:

• MS-MLPA identified methylation aberrations in 28% (9/32) of patients.
• UPD was found in 9% of cases. Aberrations included gain/loss of methylation at imprinting centers (ICs).
• WES did not reveal pathogenic variants in patients with normal MS-MLPA results. Clinical features sometimes did not fully meet SRS criteria despite molecular findings.

Conclusions:

• ILO can be considered a mild manifestation at the extreme end of the BWS spectrum.
• Approximately one-third of ILO cases exhibit methylation aberrations or UPD, necessitating careful follow-up.
• Molecular findings in ILO may not always align perfectly with established diagnostic criteria for BWS or SRS.