Investigating the "Dark" Genome: First Report of Partington Syndrome in Cyprus

Area of Science:

• Genetics and Genomics
• Neurodevelopmental Disorders
• Human Molecular Genetics

Background:

• X-linked intellectual disability (XLID) is a significant cause of intellectual disability in males, characterized by genetic heterogeneity.
• Despite advances in next-generation sequencing (NGS), many XLID cases remain genetically unresolved.
• A four-generation family presented with syndromic XLID, variable intellectual disability, focal dystonia, and epilepsy.

Purpose of the Study:

• To identify the genetic cause of XLID in a multi-affected family with a complex phenotype.
• To investigate the utility of re-analyzing underrepresented genomic regions in whole-exome sequencing (WES) and whole-genome sequencing (WGS) data.
• To establish a genotype-phenotype correlation for a newly identified variant.

Main Methods:

• Initial diagnostic evaluations included cytogenetic and targeted genetic testing.
• Whole-exome sequencing (WES) and short-read whole-genome sequencing (WGS) were performed.
• Sequencing data was re-analyzed, focusing on poorly covered regions of the X chromosome (chrX). Phenotype-driven tools (Phenomizer) were used to prioritize candidate genes.
• Variant validation and segregation analysis were conducted using Sanger sequencing.

Main Results:

• Standard diagnostic and NGS analyses did not yield a diagnosis.
• Manual inspection of low-coverage regions on chrX revealed a recurrent pathogenic ARX variant, NM_139058.3:c.441_464dup p.(Ala148_Ala155dup) (ARXdup24).
• ARXdup24 was identified in all affected males and carrier status was confirmed in unaffected mothers, segregating with the XLID phenotype, including Partington syndrome.
• This variant was previously associated with syndromic and non-syndromic XLID.

Conclusions:

• The pathogenic ARXdup24 variant was identified, resolving a long-standing diagnostic challenge for the family.
• This study establishes the first reported family with Partington syndrome in Cyprus, demonstrating a clear genotype-phenotype correlation.
• Re-evaluation of underrepresented genomic regions in sequencing data is crucial for diagnosing complex genetic disorders like XLID.