Abstract Details

Title HYPK in Humans: The First Characterization of a New Neurodevelopmental Syndrome

Topic Child Neurology and Developmental Neurology

Presentation(s) P1 - Poster Session 1 (8:00 AM-9:00 AM)

Poster/Presentation
Number 8-009

Objective

We report the first known case of a de novo HYPK variant presenting with developmental delay, autism, and facial dysmorphia.

Background HYPK is a critical modulator and inhibitor of the NatA complex, which mediates approximately 50% of all N-terminal acetylations. Mutations in other NatA complex genes, such as NAA10 and NAA15, are known to cause varying degrees of intellectual disability, hypotonia, cardiac abnormalities, and seizures. The clinical effects of pathogenic HYPK mutations, however, have not been reported previously.

Design/Methods This is a case report study with biochemical characterization of HYPK. This proband was a referral following identification of a de novo missense p. R70I variant in HYPK on trio exome sequencing. We collected extensive clinical history and conducted facial gestalt analysis. To assess how this proband’s R70I mutation affects HYPK regulatory function, we used a recently developed in-vitro assay.

Results We identified developmental and motor delays, as well as dysmorphic facial features, in this proband with a known HYPK mutation. Facial gestalt GestaltMatcher, a machine-learning algorithm trained to detect rare genetic disorders from abnormal facies, showed features similar to those seen in probands with NAA10 and NAA15 mutations, suggesting a similar pathophysiologic mechanism. Biochemical analysis showed that the R70I mutation enhanced inhibitory effects of HYPK on the NatA complex through a gain-of-function mutation.

Conclusions Our findings provide the first phenotypic characterization of a pathogenic HYPK variant and elucidate its molecular basis, which we hope will facilitate future diagnosis and management in similar cases globally.

Authors/Disclosures
Rahi Patel PRESENTER	Miss Patel has nothing to disclose.
Rikhil Makwana	Mr. Makwana has nothing to disclose.
Elaine J. Marchi	Ms. Marchi has nothing to disclose.
Ziyi Fan	Mr. Fan has nothing to disclose.
Erin Falsey	Ms. Falsey has nothing to disclose.
Beatriz Menendez, MS, CGC	Ms. Menendez has nothing to disclose.
Philip F. Giampietro, MD	Dr. Giampietro has nothing to disclose.
Ingrid M. Wentzensen, MD	Dr. Wentzensen has received personal compensation for serving as an employee of GeneDx. Dr. Wentzensen has stock in GeneDx.
Tzung-Chien Hsieh, PhD	Dr. Hsieh has nothing to disclose.
Shu-ou Shan, PhD	Dr. Shan has nothing to disclose.
GHOLSON J. LYON, MD, PhD	Prof. LYON has nothing to disclose.

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