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Pleiotropy

Pleiotropy

Pleiotropy is the phenomenon in which a single gene impacts multiple, seemingly unrelated phenotypic traits. For example, defects in the SOX10 gene cause Waardenburg Syndrome Type 4, or WS4, which can cause defects in pigmentation, hearing impairments, and an absence of intestinal contractions necessary for elimination. This diversity of phenotypes results from the expression pattern of SOX10 in early embryonic and fetal development. SOX10 is found in neural crest cells that form melanocytes,...

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Phenotypic and Imaging Spectrum Associated With WDR45.

Laura A Adang¹, Amy Pizzino¹, Alka Malhotra²

¹Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.

Pediatric Neurology

|May 11, 2020

Summary

Mutations in the WDR45 gene cause a rare neurodegenerative disorder. Early developmental delay and seizures are common, followed by progressive neurological decline, emphasizing the need for timely WDR45 genetic testing.

Keywords:

Developmental delay Epileptic encephalopathy Hypomyelination WDR45

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Area of Science:

Neurogenetics
Neurodegenerative Diseases
Developmental Biology

Background:

X-linked WDR45 gene mutations are linked to neurodegeneration with brain iron accumulation type 5 (NBIA5).
NBIA5 presents with early global developmental delay, progressing to dystonia, parkinsonism, and dementia due to brain iron buildup.

Purpose of the Study:

To analyze clinical and genetic data from a cohort of NBIA5 patients.
To better understand the phenotypic variability and diagnostic challenges associated with WDR45 mutations.

Main Methods:

Retrospective review of 17 new and 106 previously reported NBIA5 cases.
Molecular diagnosis primarily through whole-exome sequencing.
Detailed collection of developmental history and clinical outcomes.

Main Results:

10 novel WDR45 variants identified in 11 subjects.
Developmental delay, particularly in verbal skills, was universal.
Progressive motor and cognitive decline, variable seizure presentations, and evolving neuroimaging findings were observed.
Iron accumulation in basal ganglia correlated with older age; myelination abnormalities with younger age.

Conclusions:

WDR45 mutations cause a progressive, variable neurodegenerative disorder often diagnosed late.
Early symptoms include developmental delay and seizures, followed by neurological decline.
Consider WDR45 in children with myelination abnormalities, iron deposition, developmental delay, and epilepsy.