Novel Insights: A Novel PHIP Variant in a Family with Severe Early-Onset Obesity

Area of Science:

• Genetics
• Pediatrics
• Endocrinology

Background:

• Severe childhood obesity can stem from genetic factors, including monogenic and syndromic forms.
• Heterozygous variants in the pleckstrin homology domain interacting protein (PHIP) gene have been recently associated with obesity within Chung-Jansen syndrome.

Purpose of the Study:

• To investigate the genetic basis of severe early-onset obesity in a pediatric patient.
• To identify novel pathogenic variants in genes associated with obesity and developmental disorders.

Main Methods:

• Whole-exome sequencing was performed on an index patient presenting with severe obesity, developmental delay, and dysmorphic features.
• Segregation analysis was conducted in family members to confirm the inheritance pattern of the identified variant.
• In silico tools were used to predict the pathogenicity of the novel PHIP variant.

Main Results:

• A novel missense variant (c.3182C>A, p.Ala1061Glu) in the PHIP gene was identified in the index patient.
• The PHIP variant segregated with severe childhood obesity and developmental delay/learning difficulties in the patient's brother and mother.
• The identified variant affects a highly conserved residue and was predicted to be pathogenic.

Conclusions:

• Early-onset obesity can have a monogenic cause.
• This finding broadens the known spectrum of disease-causing PHIP variants.
• Variable expressivity and severity of clinical features were observed within the family.
• Genetic screening for PHIP variants is recommended for patients with severe early-onset obesity.