A 2 year old male presents with early onset seizures and global developmental delay

Can you solve the case?

Review the case background and choose from the test options below

How quickly can you reach a diagnosis?
Begin

A 2 year old male presents with early onset seizures and global developmental delay

Can you solve the case?

Review the case background and choose from the test options below

How quickly can you reach a diagnosis?
Begin

Clinical and family history

4 weeks  

Tonic clonic seizures

2 months

Global developmental delay
2 months

Difficulty swallowing, unable to sit or roll over. Right side seems stronger than his left, cortical visual impairment, hypotonia, abnormal, electroencephalogram [EEG] relative microcephaly

Summary of testing performed

CSF shows low HVA, 5-HIAA, BH4 and neopterin which may suggest a defect in the pterin biosynthetic pathway and synthesis of dopamine and serotonin. This pattern of metabolites is indicative of GTP cyclohydrolase deficiency in the autosomal dominant form. CSF 5-MTHF is normal. 

In this sample the excretions of creatine, guanidinoacetic acid and creatinine were within the respective reference ranges. 

No results, sample too diluted 

Within normal range

Normal

  • Lactic/pyruvic aciduria
  • Ketonuria
  • Dicarboxylic aciduria and branched chain ketoaciduria suggesting severe catabolic state
  • P-hydroxypheynlacetic and 3-hydroxy-propionic acids increased
  • 3-methylglutaconic acid was mildly increased without increased 3-hydroxy-isovaleric acid

All values within normal limits

Family history

  • Both parents and siblings are healthy

4 weeks

Tonic clonic seizures

2 months

Global developmental delay
22 months

Difficulty swallowing, unable to sit or roll over. Right side seems stronger than his left, cortical visual impairment, hypotonia, abnormal, electroencephalogram [EEG] relative microcephaly

Summary of testing performed

CSF shows low HVA, 5-HIAA, BH4 and neopterin which may suggest a defect in the pterin biosynthetic pathway and synthesis of dopamine and serotonin. This pattern of metabolites is indicative of GTP cyclohydrolase deficiency in the autosomal dominant form. CSF 5-MTHF is normal. 

In this sample the excretions of creatine, guanidinoacetic acid and creatinine were within the respective reference ranges. 

No results, sample too diluted 

Within normal range

Normal

  • Lactic/pyruvic aciduria
  • Ketonuria
  • Dicarboxylic aciduria and branched chain ketoaciduria suggesting severe catabolic state
  • P-hydroxypheynlacetic and 3-hydroxy-propionic acids increased
  • 3-methylglutaconic acid was mildly increased without increased 3-hydroxy-isovaleric acid

All values within normal limits

Family history

  • Both parents and siblings are healthy

Which one of the following tests would you order as the next step?

Chromosomal Microarray Analysis

You’ve ordered a Chromosomal Microarray Analysis (CMA) that provides comprehensive genetic testing for copy number variants and chromosomal aberrations.

This is a logical choice given the symptom of developmental delay. 

But the results are negative.

You’ve ordered a Chromosomal Microarray Analysis (CMA) that provides comprehensive genetic testing for copy number variants and chromosomal aberrations.

This is a logical choice given the symptom of developmental delay. 

But the results are negative.

Which one of the following tests would you order next?

Epilepsy Panel

 

You’ve ordered an Epilepsy Panel that covers 250 genes. This analyzes genes associated with both syndromic and nonsyndromic causes of epilepsy, a common neurological disease characterized by recurrent, unprovoked seizures.

This is a logical choice given the phenotype of severe seizures.

But the results are negative. 

You’ve ordered an Epilepsy Panel that covers 250 genes. This analyzes genes associated with both syndromic and nonsyndromic causes of epilepsy, a common neurological disease characterized by recurrent, unprovoked seizures.

This is a logical choice given the phenotype of severe seizures.

But the results are negative. 

Which one of the following tests would you order next?

Whole Exome Sequencing Analysis

You’ve ordered a Whole Exome Sequencing Analysis that detects small sequence changes in exonic regions. 

This is a logical choice given the broad differential diagnosis.

The testing identifies a de novo variant of uncertain clinical significance in the CACNG2 gene. However, there is insufficient evidence to associate this gene with the patient’s clinical symptoms.

You’ve ordered a Whole Exome Sequencing Analysis that detects small sequence changes in exonic regions. 

This is a logical choice given the broad differential diagnosis.

The testing identifies a de novo variant of uncertain clinical significance in the CACNG2 gene. However, there is insufficient evidence to associate this gene with the patient’s clinical symptoms.

Which one of the following tests would you order next?

Mitochondrial Disorder Analysis

You’ve ordered Mitochondrial Disorder Analysis that provides sequence analysis to detect variants associated with mitochondrial disease. 

This is a logical choice given the symptoms of early onset seizures and abnormal metabolic findings that lead to suspicion of a mitochondrial disorder. 

But the result is negative.

You’ve ordered Mitochondrial Disorder Analysis that provides sequence analysis to detect variants associated with mitochondrial disease. 

This is a logical choice given the symptoms of early onset seizures and abnormal metabolic findings that lead to suspicion of a mitochondrial disorder. 

But the result is negative.

Which one of the following tests would you order next?

Genomic Unity® Whole Genome Analysis

Testing identifies a de novo pathogenic deletion of 2.1 kb within the region of chromosome Xp22.13 in this individual. The deletion was identified in approximately 40% of the reads for an X-linked gene in this male patient, which indicates mosaicism for the deletion. 

This deletion spans exon 7 of the CDKL5 gene. Pathogenic variants, including deletions spanning one or more exons of this gene, are associated with X-linked dominant developmental and epileptic encephalopathy-2 (DEE2).  Affected males with mosaic pathogenic copy number variants have been reported. DEE2 is characterized by onset of seizures in the first months of life and severe global developmental delay, resulting in impaired intellectual development and poor motor control. Other features include subtle dysmorphic facial features, sleep disturbances, gastrointestinal problems and cortical visual impairment. Some treatments are available for patients with DEE2 and have been shown to reduce seizure frequency. 

Comprehensive testing with Variantyx offers a more streamlined solution for testing of genetic disorders from a single sample as opposed to the cost, delays, and emotional distress incurred to this patient while awaiting a diagnosis. Don’t get lost in a tunnel of endless iterative testing, see clearer results in less time with patient-driven comprehensive testing from Variantyx!

Congratulations, you’ve solved the case! To talk with a specialist and learn more about our Genomic Unity® testing portfolio, visit us at the Variantyx virtual NSGC booth!

Next up: learn more about Genomic Unity® Testing.

Comprehensive testing with Variantyx offers a more streamlined solution for testing of genetic disorders from a single sample as opposed to the cost, delays, and emotional distress incurred to this patient while awaiting a diagnosis. Don’t get lost in a tunnel of endless iterative testing, see clearer results in less time with
patient-driven comprehensive testing from Variantyx!

Testing identifies a de novo pathogenic deletion of 2.1 kb within the region of chromosome Xp22.13 in this individual. The deletion was identified in approximately 40% of the reads for an X-linked gene in this male patient, which indicates mosaicism for the deletion. 

This deletion spans exon 7 of the CDKL5 gene. Pathogenic variants, including deletions spanning one or more exons of this gene, are associated with X-linked dominant developmental and epileptic encephalopathy-2 (DEE2).  Affected males with mosaic pathogenic copy number variants have been reported. DEE2 is characterized by onset of seizures in the first months of life and severe global developmental delay, resulting in impaired intellectual development and poor motor control. Other features include subtle dysmorphic facial features, sleep disturbances, gastrointestinal problems and cortical visual impairment. Some treatments are available for patients with DEE2 and have been shown to reduce seizure frequency. 

Congratulations, you’ve solved the case! To talk with a specialist and learn more about our Genomic Unity® testing portfolio, visit us at the Variantyx virtual NSGC booth!

Next up: learn more about how to order Genomic Unity® Testing.

Interested in exploring the results of other testing for comparison?

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