JOURNAL ARTICLE

Rapid whole genome sequencing identifies a homozygous novel variant, His540Arg, in HSD17B4 resulting in D-bifunctional protein deficiency disorder diagnosis

Lane T Savage, Stacie D Adams, Kiely N James, Shimul Chowdhury, Surender Rajasekaran, Jeremy W Prokop, Caleb P Bupp
Cold Spring Harbor Molecular Case Studies 2020 October 28
33115767
Rapid whole genome sequencing (rWGS) allows for a diagnosis to be made quickly and impact medical management, particularly in critically ill children. Variants identified by this approach are often not identified using other testing methodologies, such as carrier screening or gene sequencing panels, targeted panels, or chromosomal microarrays. However, rWGS can identify variants of uncertain significance (VUS), which challenges clinicians in the rapid return of information to families. Here we present a case of the metabolic condition D-bifunctional protein deficiency in a neonate with epilepsy and hypotonia born to consanguineous parents. Sequencing revealed a homozygous VUS in HSD17B4, His540Arg. Preliminary results were delivered within 3 days of sample receipt. Previous parental carrier screening included the HSD17B4 gene but was reported as negative. The molecular finding directed the clinical team to assess phenotypic overlap and investigate next steps in terms of confirmation of the findings and potential medical management of the patient. Clinical metabolic testing of fatty acids confirmed the diagnosis. Computational analysis of HSD17B4 His540Arg showed the change to likely impact dimerization based on structural insights, with the histidine conserved and selected throughout all 223 species assessed for this amino acid. This variant clusters around several pathogenic and likely pathogenic variants in HSD17B4. This case demonstrates the utility of rWGS, the potential for receiving uncertain results, and the downstream implications for confirmation or rejection of a molecular diagnosis by the clinical team.

Full Text Links

Find Full Text Links for this Article

Discussion

You are not logged in. Sign Up or Log In to join the discussion.

Related Papers

Remove bar
Read by QxMD icon Read
33115767
×

Save your favorite articles in one place with a free QxMD account.

×

Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"