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.

Diagnosis.

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.

Management.

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 mosaicism, recurrence risk to sibs is estimated at 1%, and thus prenatal and preimplantation genetic testing may be considered.

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 2015, Shang 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).

Clinical Description

To date 23 individuals with PPP2R5D-related neurodevelopmental disorder have been reported [Houge et al 2015, Loveday et al 2015, Shang et al 2016, Yeung et al 2017]. Affected individuals range in age from 22 months to 53 years. Developmental delay and/or mild-to-severe intellectual disability has been reported in all individuals. Published clinical information is currently limited; it is likely that understanding of the phenotypic spectrum will evolve as additional affected individuals are identified.

The following are the most common clinical features of PPP2R5D-related neurodevelopmental disorder.

Psychosocial and cognitive development. All individuals reported to date have had developmental delay and/or intellectual disability. Developmental milestones are consistently delayed.

Although children were reported to have pronounced hypotonia, feeding difficulties were not reported as a major issue for most children. Gastric reflux was reported in one affected child [Houge et al 2015].

The age at which individuals walk independently varied widely – from age 18 months to nine years, with some individuals still unable to walk at age ten years. Six individuals were reported to walk with an ataxic gait [Houge et al 2015, Shang et al 2016].

All reported individuals had speech impairment, with a wide range of abilities. Seven individuals, ranging in age from two to 53 years, remained nonverbal. Eleven individuals were able to use words, although this ranged from two words with poor articulation at age ten years to 100-200 words and the ability to form short sentences at age 15 years. All individuals with PPP2R5D-related neurodevelopmental disorder have had issues with language development [Yeung et al 2017].

Evaluations for autism spectrum disorder (ASD) were done in eight children with PPP2R5D-related disorder. ASD was diagnosed in six of the eight children evaluated and suspected in one child who met some but not all of the DSM-IV criteria for ASD [Shang et al 2016, Yeung et al 2017]. Four children displayed behavioral issues such as tantrums, aggressiveness, trouble adjusting to new situations, and problems with impulse control [Shang et al 2016].

Macrocephaly/megalencephaly. Macrocephaly was reported in 18 of 23 individuals. Megalencephaly was specifically mentioned in two individuals. Head occipitofrontal circumference ranged from >2 to >3.8 SD above the mean in affected individuals. Congenital macrocephaly was reported in one individual [Loveday et al 2015]. The onset of macrocephaly has not been reported in most other affected individuals.

Hypotonia was reported in 17 individuals. Onset and severity were not reported.

Seizures have been reported in six individuals. Seizure types observed include generalized tonic-clonic, multifocal, complex partial, and generalized epileptic spasms. The age of onset ranged from four days to four years. Both individuals reported with megalencephaly also had epilepsy [Yeung et al 2017]. Further, two affected individuals with epilepsy were described to have mild ventricular dilatation [Houge et al 2015] and one individual with complex partial seizures had cavum septum pellucidum (a nonspecific finding) on brain imaging [Shang et al 2016].

Ophthalmologic abnormalities such as strabismus, astigmatism, esotropia, rotational nystagmus, ptosis, and myopia were reported in seven of the 18 individuals assessed [Houge et al 2015, Shang et al 2016]. One individual had cataracts at age 53 years [Houge et al 2015].

Dysmorphic facial features. Many individuals have dysmorphic facial features including hypertelorism, downslanting palpebral fissures, frontal bossing, and a long, hypotonic face. Midface hypoplasia, low-set ears, and plagiocephaly have also been reported. Two affected individuals with heights 2 SD above the mean were reported. However, dysmorphic features are mild, nonspecific, and vary widely among individuals reviewed.

Other

• Skeletal abnormalities observed in seven individuals include scoliosis, hip dysplasia, camptodactyly of the fourth toe, and middle 2/3 and 3/4 finger syndactyly [Houge et al 2015, Loveday et al 2015, Shang et al 2016].
• Endocrine abnormalities such as short stature (<3rd percentile) were observed in three individuals [Houge et al 2015, Shang et al 2016]. One individual had hypoglycemia and another was diagnosed with failure to thrive [Houge et al 2015, Shang et al 2016]. Age of onset of these conditions was unknown.
• Cardiac. Two individuals had significant cardiac abnormalities with atrial and ventricular septal defects and a bicuspid aortic valve in one individual and ventricular septal defect and patent foramen ovale in the other.
• Genital anomalies. One individual had hypospadias.

Genotype-Phenotype Correlations

There are no clear genotype-phenotype correlations as only 23 affected individuals have been reported to date.

Penetrance

There is no evidence of reduced penetrance; the majority of the reported pathogenic variants (22/23) are confirmed de novo. Parental results were not available for one affected individual.

Prevalence

The prevalence of PPP2R5D-related neurodevelopmental disorder is unknown. To date, 23 individuals with PPP2R5D-related neurodevelopmental disorder have been reported.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with PPP2R5D-related neurodevelopmental disorder, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Surveillance

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

PPP2R5D-related neurodevelopmental disorder is inherited in an autosomal dominant manner and is typically caused by a de novo pathogenic variant.

Risk to Family Members

Parents of a proband

• 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.
• Molecular genetic testing is recommended for the parents of a proband with an apparent de novo pathogenic variant.
• If the PPP2R5D pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, the pathogenic variant most likely occurred de novo in the proband. Another possible explanation is that the proband inherited a pathogenic variant from a parent with germline mosaicism. Although theoretically possible, no instances of germline mosaicism have been reported to date.
• Theoretically, if the parent is the individual in whom the PPP2R5D pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be mildly/minimally affected.

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents. If the PPP2R5D pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [Rahbari et al 2016].

Offspring of a proband. To date, individuals with PPP2R5D-related neurodevelopmental disorder are not known to have reproduced.

Other family members. Given that all probands with PPP2R5D-related neurodevelopmental disorder reported to date have the disorder as a result of a de novo PPP2R5D pathogenic variant, the risk to other family members is presumed to be low.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.

Prenatal Testing and Preimplantation Genetic Testing

Risk to future pregnancies is presumed to be low as the proband most likely has a de novo PPP2R5D pathogenic variant. There is, however, a recurrence risk (~1%) to sibs based on the theoretic possibility of parental germline mosaicism [Rahbari et al 2016]. Given this risk, prenatal testing and preimplantation genetic testing may be considered.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider use of prenatal testing to be a personal choice, discussion of these issues may be helpful.

Molecular Pathogenesis

PPP2R5D is a member of the PP2A family of phosphatases with critical roles in development, including neurodevelopment.

Gene structure. PPP2R5D comprises 16 exons. Three isoforms are described by alternative splicing.

See Table A, Gene for a detailed summary of gene and protein information.

Pathogenic variants. All known pathogenic variants to date are missense variants. Four variants (p.Glu197Lys, p.Glu198Lys, p.Glu200Lys, and p.Glu420Lys) alter a highly conserved negatively charged glutamic acid to a positively charged lysine, and are predicted to affect protein structure. Of these, p.Glu198Lys has been frequently encountered, identified in 48% (11/23) of individuals with PPP2R5D-related disorder. With the exception of variant p.Pro53Ser, pathogenic variants showed deficient holoenzyme formation in HEK293 cells [Houge et al 2015]; p.Pro53Ser has been associated with a different phenotype including microcephaly and short stature.

No affected individuals with an isolated whole-gene or intragenic deletion or duplication of PPP2R5D have been reported, although contiguous gene deletions and duplication of 6p21.1 are reported in public databases as being associated with disease (see Genetically Related Disorders; decipher.sanger.ac.uk).

Normal gene product. PPP2R5D encodes a 602-amino acid protein B56δ, a subunit of the serine/threonine-protein phosphatase 2A (PP2A). The PP2A complex is composed of three subunits: a scaffolding subunit A, a regulatory subunit B, and a catalytic domain C. B56δ is one of the isoforms of subunit B and is highly expressed in the brain. This protein is thought to be involved in cell growth, chromatin remodeling, and transcriptional regulation. There is evidence that PP2A-B56δ holoenzyme interacts with PI3K/AKT growth regulatory cascade [Loveday et al 2015].

Abnormal gene product. The p.Glu198Lys and p.Glu200Lys disease-associated variants disrupt PP2A subunit binding and impair dephosphorylation of specific substrates [Houge et al 2015]. The p.Glu420Lys variant is positioned near an active site of the catalytic subunit and is likely to disrupt holoenzyme formation or substrate recognition [Shang et al 2016]. A dominant-negative effect is proposed, supported by biochemical evidence of B56δ-dependent PP2A dysregulation [Houge et al 2015]; however, large 6p21.1-deletion phenotypes are suggestive of a loss-of-function mechanism.

Author Notes

Dr Ghayda Mirzaa is a geneticist and researcher at the University of Washington and Seattle Children's Hospital. Her research program studies the underlying causes, natural history, and medical management of developmental brain disorders including brain growth disorders (macrocephaly and megalencephaly) and malformations of cortical development.

Mary Nattakom is a medical student at Columbia University Vagelos College of Physicians and Surgeons.

Dr Wendy Chung is a medical and molecular geneticist at Columbia University and studies the genetic basis of autism neurodevelopmental disorders, congenital anomalies, and other conditions.

Kimberly Foss, LGC is a genetic counselor at Seattle Children's Hospital and is involved in the Neurogenetics and Epilepsy Genetics clinics. She also spends time at the Seattle Children's Research Institute with the Center for Integrative Brain Research.

Acknowledgments

We thank Jordan's Guardian Angels for supporting research on PPP2R5D-related neurodevelopmental disorder.

Revision History

• 24 January 2019 (sw) Review posted live
• 7 September 2018 (kf) Original submission

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