HYPK in Humans: The First Characterization of a New Neurodevelopmental Syndrome
Rahi Patel1, Rikhil Makwana1, Elaine Marchi2, Ziyi Fan3, Erin Falsey4, Beatriz Menendez4, Philip Giampietro4, Ingrid Wentzensen5, Tzung-Chien Hsieh6, Shu-ou Shan3, GHOLSON LYON2
1Chicago Medical School, 2New York State Institute for Basic Research in Developmental Disabilities, 3California Institute of Technology, 4University of Illinois Chicago, 5GeneDx LLC, 6University Hospital Bonn
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.
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