Abby is a 6-year-old girl with a severe yet undiagnosed disease. Abby and both parents have had their genomes sequenced. They need your help.
#16 by Colby MD
Sun Jul 10, 2016 12:41 am
* If you are a researcher or healthcare provider and have a patient with a possible mutation in the HNRNPH2 gene, please contact Dr. Chung by emailing [email protected] with subject "Email for Dr. Chung - HNRNPH2". We will then put you in contact with Dr. Chung.

* If you are a parent of a child with a possible mutation in the HNRNPH2 gene, a support group is being formed so that you can communicate with other parents, healthcare providers and researchers. To join this support group, please contact Dr. Brandon Colby by emailing [email protected] with subject "Email for Dr. Colby - HNRNPH2".


Dr. Kristin Monaghan presented the following at the 2016 American College of Medical Genetics Annual Clinical Genetics Meeting in Tampa, Florida. This presentation includes the identified pathogenic variant for Abbie.

Novel X-Linked Syndrome Characterized by Neurodevelopmental Delay, Behavioral Abnormalities, Seizures, Abnormal Tone and Dysmorphic Features

We describe a novel syndrome characterized by developmental delay, intellectual disability (ID), abnormal behavior, seizures, abnormal muscle tone, and dysmorphic features due to pathogenic de novo variants in the X-linked heterogeneous nuclear ribonucleoprotein H2 (HNRNPH2) gene.

Clinical whole exome sequencing (WES) was performed on 3,818 patients with developmental delay or ID. Four affected females from four unrelated proband-parent trios were heterozygous for a de novo HNRNPH2 variant predicted to cause their phenotype. A fifth female was identified through a separate laboratory. The detected HNRNPH2 variants were absent from the NHLBI Exome Sequencing Project, 1000 Genomes and Exome Aggregation Consortium public databases as well as from our internal WES database of unaffected parents. Mutations clustered at two amino acid residues within a highly evolutionarily conserved region.

Two individuals shared the p.R206W (c.616C>T) variant, while two other individuals were heterozygous for a different missense variant at the same residue, p.R206Q (c.617G>A). The fifth individual was heterozygous for the nearby missense variant, p.P209L (c.626C>T). The patients ranged in ages from 27 months to 34 years and all are reported to have intellectual disability and/or global developmental delay.

Behavioral disturbances were noted in all cases other than the youngest child and included stereotypic or aggressive behavior, anxiety, autism, and obsessive-compulsive disorder. Neurological exams were significant for tone abnormalities, including hypotonia and hypertonia with spasticity, ataxia and gait disturbance. Three of the patients had seizures and two had microcephaly. One had documented cerebellar anomalies on brain imaging and another had a questionably distorted cerebellar vermis. Several patients had dysmorphic facial features including micrognathia,concave eyebrows, prominent fingertip pads or shortened palpebral fissures. Skeletal anomalies were common and included short stature, scoliosis, lordosis, pectus carinatum, pes planus, joint laxity, mild micrognathia and one patient with arachnodactyly. Gastroesophageal reflux disease and constipation were noted in three patients.

HNRNPH2 is a member of a family of ubiquitously expressed heterogeneous nuclear ribonucleoproteins (hnRNPs) located at Xq22.1. The hnRNPs are RNA binding proteins involved in pre-mRNA splicing leading to alternative splicing, an important mechanism in the developmental and cell-type-specific control of gene expression. Pathogenic variants in another member of the hnRNP family, HNRNPU, has been implicated in neurodevelopmental and seizure disorders.

We propose that pathogenic variants in HNRNPH2 may affect brain development and function, resulting in the phenotype described here. The findings presented in this case series may facilitate the identification of additional affected patients to further the knowledge regarding the phenotype associated with pathogenic variants in HNRNPH2.

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