Researchers have identified a gene mutation that causes neurodevelopmental syndrome


Researchers have identified a gene mutation that causes developmental delay, intellectual disability, behavioral abnormalities and musculoskeletal problems in children.

The newly diagnosed condition, called NKAP-related syndrome, arises from mutations in the NKAP gene, which plays a key role in human development.

“This gene mutation disrupts transcription, the process in which DNA information is converted into RNA,” said study leader Kosuke Izumi, MD, PhD, a clinical geneticist and genetics researcher at Children’s Hospital of Philadelphia.

“As my lab continues to explore the function of NKAP in our bodies, we aim to discover clues for future treatments.”

Izumi and co-authors from eight nations published their report of NKAP-related syndrome today in the American Journal of Human Genetics.

The scientists performed exome sequencing on 10 individuals, all children and young adults, with developmental delay, intellectual disability, behavioral problems such as ADHD and aggressive behavior, and tall stature, scoliosis and joint conditions.

The subjects’ tall stature and musculoskeletal problems are “Marfanoid”: similar to traits found in the long-known genetic disorder Marfan syndrome.

The exome sequencing pinpointed mutations in the NKAP gene on the X chromosome. Consistent with an X-linked recessive condition, NKAP mutations caused symptoms only in males.

The exome sequencing pinpointed mutations in the NKAP gene on the X chromosome. Consistent with an X-linked recessive condition, NKAP mutations caused symptoms only in males.

Further analysis showed that transcription disruption patterns were similar in the patients–a higher proportion of genes were downregulated than upregulated, that is, the mutation “dialed down” the gene’s effects on RNA and proteins.

Experiments with zebrafish models revealed similar effects from an analogous mutated gene.

“The function of NKAP in our bodies has been poorly understood,” said Izumi. “We discovered novel functions in brain and musculoskeletal development.

Furthermore, we have started a patient registry to collect clinical information on patients with this rare diagnosis. Identifying more patients may help to reveal the full spectrum of medical issues seen in NKAP-related syndrome.”

In addition to providing a definitive diagnosis to a subset of patients with developmental delay and intellectual disability found to harbor this mutation, biological insights may eventually translate into clinical benefits.

“As we further investigate biological mechanisms in this syndrome, our goal is to identify molecular pathways to target for future treatments for patients,” added Izumi.

Clinical characteristics.

PPP2R5D-related neurodevelopmental disorder is characterized by mild to severe neurodevelopmental delay. Pronounced hypotonia with delay in gross motor skills is common. Onset of independent walking varies widely and ataxia is reported. All reported individuals have speech impairment, with a wide range of abilities. Autism spectrum disorder is reported in six individuals.

Macrocephaly is common. Seizures and ophthalmologic abnormalities are reported in fewer than half of individuals. Additional anomalies include skeletal, endocrine, and cardiac malformations, each reported in a few individuals. To date, 23 individuals with PPP2R5D-related neurodevelopmental disorder have been reported.


The diagnosis of PPP2R5D-related neurodevelopmental disorder is established in a proband by identification of a heterozygous pathogenic variant in PPP2R5D on molecular genetic testing.


Treatment of manifestations: Standard treatment for seizures, visual impairment, and developmental delays.

Surveillance: Monitor for seizures, vision issues, developmental progress, and educational needs.

Genetic counseling.

PPP2R5D-related neurodevelopmental disorder is inherited in an autosomal dominant manner. All probands reported to date with PPP2R5D-related neurodevelopmental disorder whose parents have undergone molecular genetic testing have the disorder as a result of a de novo PPP2R5D pathogenic variant. Risk to future pregnancies is presumed to be low, as the proband most likely has a de novo PPP2R5D pathogenic variant; however, given the theoretic possibility of parental germline mosaicismrecurrence risk to sibs is estimated at 1%, and thus prenatal testing for pregnancies at risk and preimplantation genetic diagnosis may be considered.Go to:


Formal diagnostic criteria for PPP2R5D-related neurodevelopmental disorder have not been established.

Suggestive Findings

PPP2R5D-related neurodevelopmental disorder should be considered in individuals presenting with the following clinical and brain MRI findings.

Clinical findings

  • Macrocephaly
  • Generalized hypotonia of infancy
  • Mild-to-profound developmental delays or intellectual disability
  • Autism spectrum disorder
  • Epilepsy (reported seizure types: generalized tonic-clonic, multifocal, complex partial, and generalized epileptic spasms)

Brain MRI findings

  • Megalencephaly
  • Nonspecific MRI findings include: hydrocephalus (2 individuals), mild-to-moderate ventricular dilatation (4 individuals), small or dysplastic corpus callosum (2), cavum septum pellucidum (1), cavum septum pellucidum et vergae (1), and white matter abnormalities (1) [Houge et al 2015Shang et al 2016].

Establishing the Diagnosis

The diagnosis of PPP2R5D-related neurodevelopmental disorder is established in a proband by identification of a heterozygous pathogenic variant in PPP2R5D by molecular genetic testing (see Table 1).

Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel) and comprehensive genomic testing (typically exome sequencing).

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of PPP2R5D -related neurodevelopmental disorder is nonspecific and indistinguishable from many other inherited disorders, it is most likely to be diagnosed by either a multigene panel (see Option 1) or genomic testing (see Option 2).

Media Contacts:
John Ascenzi – CHOP
Image Source:
The image is in the public domain.

Original Research: Closed access
“Missense Mutations in NKAP Cause a Disorder of Transcriptional Regulation Characterized by Marfanoid Habitus and Cognitive Impairment”. Sarah K. Fiordaliso et al.
American Journal of Human Genetics doi:10.1016/j.ajhg.2019.09.009.


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