Expanding the Clinical Spectrum Associated with the Recurrent Arg203Trp Variant in PACS1: An Italian Cohort Study

Area of Science:

• Genetics
• Neurodevelopmental Disorders
• Rare Diseases

Background:

• Schuurs-Hoeijmakers syndrome (SHMS), also known as PACS1 neurodevelopmental disorder, is a rare genetic condition.
• It is associated with intellectual disability, craniofacial abnormalities, and congenital malformations.
• Previous studies identified PACS1 gene variants in 63 patients.

Purpose of the Study:

• To describe 10 new Italian patients with SHMS.
• To detail the clinical features of SHMS.
• To facilitate the diagnosis and management of SHMS.

Main Methods:

• Clinical evaluation by geneticists and child neurologists.
• Phenotypic data coded using Human Phenotype Ontology (HPO) terms.
• Identification of the recurrent p.(Arg203Trp) PACS1 variant via exome sequencing and a novel PCR-RFLP strategy.

Main Results:

• Detailed clinical phenotyping of 10 Italian SHMS patients with the p.(Arg203Trp) variant.
• Identified characteristic facial features: thick eyebrows, down-slanting palpebral fissures, ocular hypertelorism, low-set ears, thin upper lip, wide mouth.
• These features aid in diagnosis through clinical evaluation, neuroimaging, and neuropsychological assessment.

Conclusions:

• The study highlights specific clinical features aiding SHMS recognition in Italian children.
• Improved diagnostic capabilities can lead to better management strategies.
• Findings contribute to precision medicine approaches in medical genetics for SHMS.