What clinical manifestations and management should be considered for a patient with a 12q24.21 deletion involving the MED13L gene and a 6q26 deletion involving the PRKN (PARK2) gene?

12q24.21 Deletion (MED13L Gene) and 6q26 Deletion (PRKN Gene)

These are two distinct genetic deletions that require separate clinical evaluation and management, as they involve different chromosomal regions with unrelated pathophysiology—the 12q24.21 deletion affecting the MED13L gene causes a recognizable neurodevelopmental syndrome, while the 6q26 deletion affecting PRKN (PARK2) is primarily associated with early-onset Parkinson disease and has emerging associations with autism spectrum disorder.

12q24.21 Deletion Involving MED13L Gene

Clinical Manifestations

• Neurodevelopmental features are the hallmark, including developmental delay and intellectual disability, which are the most commonly described clinical features in patients with 12q21 interstitial deletions 1
• Congenital malformations may include:
  • Genitourinary malformations 1
  • Brain malformations 1
  • Cardiac defects (less frequent but documented) 1
• Additional features that may present include:
  • Hearing loss 1
  • Hypotonia 1
  • Dysmorphic facial features 1

Management Approach

• Comprehensive developmental assessment at diagnosis to establish baseline cognitive and adaptive functioning 1
• Neuroimaging (brain MRI) to evaluate for structural brain malformations 1
• Cardiac evaluation with echocardiogram to screen for congenital heart defects 1
• Renal ultrasound to assess for genitourinary malformations 1
• Audiological assessment to detect hearing impairment 1
• Early intervention services including physical therapy, occupational therapy, and speech-language therapy for developmental delays 1
• Genetic counseling for the family regarding recurrence risk and inheritance pattern 1

Critical Considerations

• The deletion size and specific genes involved outside the critical region may correlate with additional clinical features beyond the core phenotype 1
• This is a gene-poor region of chromosome 12q, making genotype-phenotype correlations challenging 1

6q26 Deletion Involving PRKN (PARK2) Gene

Clinical Manifestations

• Early-onset Parkinson disease is the primary association:
  • Biallelic PARK2 mutations (homozygous or compound heterozygous) cause autosomal recessive juvenile parkinsonism and young-onset Parkinson disease with onset typically before age 30 2
  • Age at onset ranges from 20 to 76 years in mutation carriers 3
  • Patients with compound heterozygous mutations have significantly earlier disease onset compared to heterozygotes (p = 0.001) 2
• Heterozygous carrier effects:
  • Single PARK2 mutation carriers have an 11.7-year earlier age at onset compared to non-carriers (p = 0.04) 3
  • Heterozygosity influences Parkinson disease penetrance even in familial cases 3
• Neurodevelopmental associations (emerging evidence):
  • PARK2 copy number variants have been implicated in autism spectrum disorder 4, 5
  • Associations with schizophrenia and ADHD have been reported 4
  • Deletions involving exons 5-12 may be more deleterious and cause a unique neurological syndrome 4

Molecular Considerations

• Deletion/duplication effects:
  • Both deletions and duplications can disrupt PARK2 function 5
  • Exonic duplications may cause more severe interference with PARK2 expression than deletions at the same exons 5
  • PARK2 expression is down-regulated in an exon-dependent manner with either deletion or duplication 5
• Mutation spectrum:
  • Over 100 different PARK2 variants have been reported, including point mutations, small indels, and copy number variations 2
  • Sequence and dosage variants are equally represented in affected patients 2

Management Approach

• Neurological evaluation with focus on:
  • Movement disorder assessment, particularly for parkinsonian features 3, 2
  • Age-appropriate motor function testing 2
  • Baseline neurological examination even in asymptomatic children 4
• Neurodevelopmental screening for:
  • Autism spectrum disorder features 4, 5
  • Attention and behavioral concerns 4
  • Cognitive development 4
• Genetic counseling addressing:
  • Autosomal recessive inheritance pattern for Parkinson disease (requires biallelic mutations) 3, 2
  • Risk assessment for family members 3
  • Parental testing to determine inheritance pattern (de novo vs. inherited) 4
• Long-term monitoring:
  • Serial neurological examinations throughout childhood and into adulthood 3, 2
  • Vigilance for early parkinsonian signs, especially if biallelic mutations are present 2
  • Developmental surveillance if neurodevelopmental features are present 4, 5

Critical Pitfalls to Avoid

• Do not assume that a single PARK2 deletion is clinically insignificant—heterozygous carriers have earlier Parkinson disease onset 3
• Do not delay comprehensive genetic testing to determine if the deletion is heterozygous or part of compound heterozygosity, as this dramatically affects prognosis 2
• Do not overlook neurodevelopmental screening in children with PARK2 deletions, as the gene has broader neurological implications beyond Parkinson disease 4, 5

Combined Genetic Counseling Considerations

• These deletions are unrelated and should be counseled separately with distinct recurrence risks 3, 1
• Parental testing is essential for both deletions to determine inheritance pattern and recurrence risk 4, 1
• Comprehensive documentation of family history for both neurodevelopmental disorders and movement disorders is critical 3, 1