Ataxia with Oculomotor Apraxia Type 4 with PNKP Common "Portuguese" and Novel Mutations in Two Belarusian Families

Area of Science:

• Genetics and Neurology
• Rare Genetic Disorders

Background:

• Ataxia with oculomotor apraxia type 4 (AOA4) is a rare autosomal recessive disorder linked to the PNKP gene, first identified in Portugal in 2015.
• Previous research has primarily focused on European populations, leaving the genetic landscape of AOA4 in other ethnic groups largely unexplored.

Purpose of the Study:

• To diagnose and characterize Ataxia with oculomotor apraxia type 4 (AOA4) in Slavic patients.
• To identify novel mutations in the PNKP gene associated with AOA4 in Belarusian families.
• To investigate the genetic overlap and phenotypic distinctions between AOA4 and other PNKP-related disorders.

Main Methods:

• Next-generation sequencing (NGS) was employed for initial genetic screening.
• Sanger sequencing was utilized for confirmation of identified mutations in three affected boys from two unrelated Belarusian families.
• Genetic analysis focused on the PNKP gene, identifying heterozygous and biallelic mutations.

Main Results:

• The study successfully diagnosed AOA4 in three Belarusian boys, marking the first reported Slavic cases of this disorder.
• A common Portuguese PNKP mutation (c.1123G>T) was identified in heterozygous form in both families.
• Novel biallelic PNKP mutations (c.1270_1283dup14 and c.1029+2T>C) were discovered, expanding the known mutation spectrum for AOA4.

Conclusions:

• This research establishes the presence of Ataxia with oculomotor apraxia type 4 (AOA4) in Slavic populations and highlights the first occurrence of a 'Portuguese' PNKP mutation outside Portugal.
• The findings underscore the importance of broad ethnic screening for rare genetic disorders like AOA4 to understand global genetic diversity.
• Phenotypic variations, including microcephaly, were observed, suggesting a spectrum of clinical presentations within PNKP-related neurological disorders.