POLA1 – Van Esch-O’Driscoll syndrome

Van Esch-O’Driscoll syndrome is a syndromic form of X-linked intellectual disability characterized by short stature, microcephaly, variable degrees of intellectual disability, and hypogonadotropic hypogonadism. The disease is caused by hemizygous hypomorphic variants in POLA1, encoding the catalytic subunit of DNA polymerase α, essential for DNA replication initiation and genome stability. Female carriers are generally unaffected, supporting a strictly X-linked recessive mechanism of disease.

Genetic Evidence

POLA1-related Van Esch-O’Driscoll syndrome is inherited in an X-linked recessive manner with affected males harboring hemizygous hypomorphic POLA1 variants. To date, 10 male probands from 6 unrelated families have been reported, including a three-year-old child with a novel splice site variant causing exon 6 skipping and reduced POLA1 expression (PMID:34119699). Segregation of POLA1 variants with disease was observed in 5 additional affected male relatives across these families (PMID:34119699).

Variant Spectrum

Reported disease-causing alleles are hypomorphic missense and splice site variants that reduce POLA1 catalytic activity or expression. Representative variants include c.2590C>T (p.Leu864Phe), shown to impair nucleotide discrimination and increase replication errors in vitro (PMID:20202915). No recurrent founder alleles have been described to date.

Functional Evidence

Hypomorphic POLA1 variants identified in patients lead to reduced polymerase α activity, as demonstrated by exon skipping and downregulated POLA1 levels in patient cells (PMID:34119699). In vitro assays of the p.Leu864Phe variant show a 180-fold increase in mutation rate and decreased nucleotide discrimination, confirming a loss-of-function mechanism consistent with the human phenotype (PMID:20202915).

Conflicting Evidence

A three-generation family with a heterozygous deletion of POLA1 in females manifests only subfertility, without signs of Van Esch-O’Driscoll syndrome, underscoring early male lethality of null alleles and lack of VEODS in female carriers with skewed X-inactivation (PMID:36182037).

Integration & Clinical Utility

Collectively, genetic segregation in multiple families and concordant functional data support a Strong clinical validity for the POLA1–Van Esch-O’Driscoll syndrome association. The evidence meets ClinGen criteria for X-linked recessive disorders with hypomorphic POLA1 variants. Diagnostic testing for POLA1 should be considered in males with the characteristic VEODS phenotype, and genetic counseling must address male-lethality of null alleles and subfertility in female carriers.

Key Take-home: Hemizygous hypomorphic POLA1 variants cause Van Esch-O’Driscoll syndrome via reduced polymerase α activity, with clear X-linked recessive inheritance and early male lethality of null alleles.

References

• European journal of medical genetics • 2021 • A patient with POLA1 splice variant expands the yet evolving phenotype of Van Esch-O’Driscoll syndrome. PMID:34119699
• European journal of medical genetics • 2022 • A Xp22.11-p21.3 microdeletion in a three-generation family supports male lethality of POLA1 nullisomy resulting in reduced fertility of female carriers. PMID:36182037
• DNA repair • 2010 • Functions of base selection step in human DNA polymerase alpha. PMID:20202915

Evidence Based Scoring (AI generated)