PPP2R1A-Related Neurodevelopmental Disorder

Clinical characteristics.

PPP2R1A-related neurodevelopmental disorder (NDD) is characterized by: severe, persistent hypotonia; developmental delay with variable intellectual outcomes, typically in the moderate-to-severe intellectual disability range; seizures (more commonly seen in individuals with microcephaly and/or severe intellectual disability); attention-deficit/hyperactivity disorder and other behavioral problems (anxiousness, repetitive movements, self-injurious or destructive behavior, and autism spectrum disorder); feeding and swallowing issues; and dysmorphic features of the head and face. A minority of affected individuals have ear anomalies, hearing loss, ptosis, generalized joint hypermobility, and patent ductus arteriosus. Brain MRI findings are nonspecific but typically include complete or partial agenesis of the corpus callosum. Nonprogressive ventriculomegaly may be seen in a subset of affected individuals and is often associated with specific pathogenic variants in PPP2R1A: c.544C>T (p.Arg182Trp) and c.547C>T (p.Arg183Trp).

Diagnosis/testing.

The diagnosis of PPP2R1A-NDD is established in a proband with suggestive clinical findings and a heterozygous pathogenic variant in PPP2R1A identified by molecular genetic testing.

Management.

Treatment of manifestations: Feeding therapy with consideration of gastrostomy tube placement for persistent feeding issues; standard treatment for epilepsy, developmental delay / intellectual disability, scoliosis, ear anomalies, hearing loss, dental crowding, congenital heart defects, and ptosis.

Surveillance: At each visit: measure growth parameters; evaluate nutritional status and oral intake; assess for new neurologic manifestations such as seizures and changes in muscle tone; monitor developmental progress and educational needs; assess mobility, self-help skills, and need for developmental therapies. At each visit until skeletal maturity: physical exam to assess for scoliosis. Annually or as clinically indicated: dental evaluation, audiology evaluation (through childhood), and behavioral assessment for anxiety, attention, and aggressive or self-injurious behavior.

Genetic counseling.

PPP2R1A-related NDD is expressed in an autosomal dominant manner and typically caused by a de novo PPP2R1A pathogenic variant. The risk to other family members is presumed to be low. Once a PPP2R1A pathogenic variant has been identified in an affected family member, prenatal testing and preimplantation genetic testing are possible.

Suggestive Findings

PPP2R1A-related neurodevelopmental disorder (PPP2R1A-NDD) should be considered in individuals with the following clinical and brain imaging findings.

Clinical findings include:

• Mild-to-profound developmental delay and/or intellectual disability
  • Delayed walking
  • Language delay
• Generalized hypotonia, postnatal/infantile onset

AND any of the following features presenting in infancy or childhood:

• Feeding problems
• Abnormal head circumference (macrocephaly/microcephaly)
• Epilepsy
• Behavioral problems: attention-deficit/hyperactivity disorder, autism spectrum disorder, self-injurious behavior, anxiety, destructive behaviors
• Joint hypermobility

Brain MRI findings

• Partial or complete agenesis of the corpus callosum (common)
• Ventriculomegaly (frequent)
• Periventricular leukomalacia
• Delayed myelination
• Hypoplasia of the cerebellum and/or brain stem

Family history. All cases to date have been caused by a de novo pathogenic missense variant in PPP2R1A. All probands so far represent simplex cases (i.e., a single occurrence in a family). Since the severity of the condition is so variable and correlated to the degree of biochemical disturbance, a milder end of the phenotypic spectrum compatible with autosomal dominant inheritance from a mildly affected parent may in theory exist.

Establishing the Diagnosis

The diagnosis of PPP2R1A-NDD is established in a proband with suggestive clinical findings and a heterozygous pathogenic (or likely pathogenic) variant in PPP2R1A identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) Identification of a heterozygous PPP2R1A variant of uncertain significance (VUS) does not establish or rule out the diagnosis of this disorder. Biochemical testing to investigate the pathogenicity of a VUS is cumbersome and is currently only done in a research setting.

Molecular genetic testing in a child with developmental delay or an older individual with intellectual disability may begin with chromosomal microarray analysis (CMA). Other options include use of a multigene panel or exome sequencing. Note: Because of the nonspecific nature of the presenting clinical features, single-gene testing (sequence analysis of PPP2R1A, followed by gene-targeted deletion/duplication analysis) is rarely useful and typically NOT recommended.

• An intellectual disability multigene panel that includes PPP2R1A and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition in a person with a nondiagnostic CMA while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
• Comprehensive genomic testing does not require the clinician to determine which gene(s) are likely involved. Exome sequencing is most commonly used and yields results similar to an intellectual disability multigene panel with the additional advantage that exome sequencing includes genes that may have been recently identified as causal of neurodevelopmental disorders, whereas some multigene panels may not.
  Genome sequencing is also possible.
  For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in PPP2R1A-Related Neurodevelopmental Disorder

Clinical Description

To date, fewer than 50 individuals have been identified with a pathogenic variant in PPP2R1A [Houge et al 2015, Wallace et al 2019, Stenson et al 2020, Zhang et al 2020, Lenaerts et al 2021]. The following description of the phenotypic features associated with this condition is based on comprehensive clinical observations of individuals with confirmed pathogenic variants.

Table 2.

Select Features of PPP2R1A-Related Neurodevelopmental Disorder

Developmental delay (DD) and intellectual disability (ID). The degree of DD is variable, but often in the moderate-to-severe range. DD in most affected individuals is global, affecting both cognitive and motor skills, but speech and language development and walking appear to be especially delayed.

• The most severely affected individuals are typically nonambulatory, and those who learned to walk did so between ages one and five years (average age ~2 years).
• Delayed/absent ambulation could be related to chronic hypotonia seen in most affected individuals.
• One individual did not have ID but had a full-scale IQ of 86 and a clinical diagnosis of autism spectrum disorder [Lenaerts et al 2021]; otherwise, all reported individuals have cognitive performance that falls within the range of ID (defined as a full-scale IQ score of <70).

Language delays are similarly variable, ranging from individuals with no speech and language development to those with relatively normal verbal language skills, but on average language development is moderately to severely delayed.

Hypotonia is a common feature, and unlike the transient neonatal hypotonia that is a feature of numerous syndromes, PPP2R1A-related hypotonia is long-lasting and possibly permanent.

Epilepsy is present in about half of affected individuals and is often associated with moderate-to-severe ID.

• Individuals with microcephaly appear to be at an increased risk for developing epilepsy.
• Most individuals with epilepsy develop seizures within the first year of life.
• Seizure types and frequency are variable.
  • In a few individuals, seizures are multifocal and refractory to treatment.
  • The authors are aware of four children who died at young ages as a result of severe epilepsy-associated brain dysfunction; all had pathogenic variants involving p.Arg183 (c.547C) (see also Genotype-Phenotype Correlations).

Behavior problems. Problems related to behavior and sleep were variably present but not in all individuals. The most common is attention-deficit/hyperactivity disorder, but anxiousness, repetitive movements, self-injurious or destructive behavior, and autism spectrum disorders have also been reported. Behavior problems are more commonly observed in those with epilepsy [Lenaerts et al 2021].

Feeding and growth

• Feeding difficulties have been reported in about half of affected individuals and tend to be more common in those who are more severely affected.
  • Swallowing difficulties have been reported, causing gagging and/or choking with solid foods and necessitating soft or pureed foods.
  • Some affected individuals have gastroesophageal reflux disease that requires treatment (see Management).
  • High palate (which can be associated with dental crowding) has been observed and contributes to feeding difficulties.
  • The severity is variable, but some individuals need gastrostomy tube placement.
• Head circumference. Approximately two thirds of affected individuals present with abnormal head circumference, either macrocephaly (33%) or microcephaly (28%), which is usually congenital. While macrocephaly is usually nonprogressive, microcephaly can be progressive.
  • Most of the individuals with increased head size (macrocephaly) present with true megalencephaly, with a head circumference >3 SD and as high as 5.23 SD above the mean for age and sex in the absence of ventriculomegaly or hydrocephalus.
  • In individuals with microcephaly, head circumference is 3-6 SD below the mean for age and sex.
  • Some pathogenic variants are specifically associated with megalencephaly and moderate ID or with microcephaly (see Genotype-Phenotype Correlations).
• Length/height was within normal range in nearly 90% of affected individuals, and quite variable in individuals with the same pathogenic variant. Fewer than 10% have short stature (defined as length/height 2 SD below the mean for age and sex), and one had tall stature (defined as length/height 2 SD above the mean for age and sex) [Lenaerts et al 2021].

Ears

• Hearing loss has been reported in a minority (~10%) of individuals with PPP2R1A-NDD [Zhang et al 2020, Lenaerts et al 2021]. In two individuals, the hearing loss was described as sensorineural; in another two individuals it was associated with microtia.
• A range of external ear abnormalities not associated with hearing loss including low-set, small, cupped, simple, and asymmetric ears have also been reported.

Eyes. Although cortical blindness has been suspected in a few infants with severe features of PPP2R1A-NDD, no verified reports of eye or visual problems exist. However, ptosis can occur (probably as part of general muscular hypotonia).

Neuroimaging. Approximately two thirds of affected individuals have corpus callosum hypoplasia or aplasia, although almost one third have normal brain MRI findings.

• In a number of individuals, ventriculomegaly was identified and may be associated with a specific pathogenic variant (see Genotype-Phenotype Correlations).
  • In two of these individuals the detection of severe ventriculomegaly led to a suspicion of hydrocephalus and ventriculoperitoneal shunting.
  • However, there is to date no confirmation of progressive ventriculomegaly or hydrocephalus.
• Less frequent findings include:
  • Delayed myelination
  • Hypoplasia of the cerebellum and/or brain stem
  • Periventricular leukomalacia

Other associated features

• Musculoskeletal features. In addition to hypotonia, generalized joint hypermobility and scoliosis have been reported in about one third of individuals. In two severely affected individuals, hip dislocations were also reported; one of the two also had a knee dislocation.
• Cardiovascular. Persistent ductus arteriosus has been reported in three affected individuals (8%).
• Facial features. Facial dysmorphism is frequently seen and can be partly associated with generalized hypotonia. Recurrent features include a long face with a tall forehead or frontal bossing (especially in those with macrocephaly), widely spaced eyes (hypertelorism), short palpebral fissures, a small nose with bulbous/prominent nasal tip, tented and/or thin vermilion of the upper lip, and, occasionally, ptosis [Lenaerts et al 2021].

Prognosis. The life span of severely affected individuals with PPP2R1A-NDD can be shortened, especially in the presence of severe epilepsy that is refractory to treatment [Authors, personal communication]. In individuals with milder features, there are no life-limiting clinical comorbidities. Among the few reported individuals with PPP2R1A-NDD, several are in their third decade and not affected by life-limiting health problems [Lenaerts et al 2021]. Even though many PPP2R1A missense variants are also found somatically in tumors (see Cancer and Benign Tumors), no evidence so far would indicate that PPP2R1A-NDD is a cancer predisposition syndrome.

Genotype-Phenotype Correlations

Individuals with a heterozygous pathogenic variant that does not affect PPP2R1A binding to PPP2R2A (B55α) – for example, c.421T>A (p.Phe141Ile), c.532A>T (p.Thr178Ser), c.533C>A (p.Thr178Asn), c.539T>C (p.Met180Thr), and c.538A>G (p.Met180Val) – are more likely to have the following [Lenaerts et al 2021]:

• Macrocephaly, defined as head circumference >2 SD for age and sex
• Less severe intellectual disability
• No seizures
• Frontal bossing / long face

Individuals with pathogenic missense variants that are more likely to cause severe epilepsy – for example, c.536C>T (p.Pro179Leu), c.544C>T (p.Arg182Trp), and c.547C>T (p.Arg183Trp) – are also more likely to have more severe intellectual disability [Lenaerts et al 2021].

Microcephaly is most often associated with the following pathogenic missense variants: c.536C>T (p.Pro179Leu), c.773G>A (p.Arg258His), and c.772C>A (p.Arg258Ser).

Most individuals with the pathogenic variants c.544C>T (p.Arg182Trp) and c.547C>T (p.Arg183Trp) have ventriculomegaly.

Prevalence

The prevalence of PPP2RA1-NDD is unknown. To date, about 40 individuals have been reported in the literature and about ten more are known (DECIPHER; Authors, personal communications), with a total of around 50 known affected individuals.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with PPP2R1A-NDD, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to diagnosis) are recommended.

Table 4.

Recommended Evaluations Following Initial Diagnosis in Individuals with PPP2R1A-Related Neurodevelopmental Disorder

Treatment of Manifestations

Table 5.

Treatment of Manifestations in Individuals with PPP2R1A-Related Neurodevelopmental Disorder

Surveillance

Table 6.

Recommended Surveillance for Individuals with PPP2R1A-Related Neurodevelopmental Disorder

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

PPP2R1A-related neurodevelopmental disorder (PPP2R1A-NDD) is an autosomal dominant disorder typically caused by a de novo pathogenic variant.

Risk to Family Members

Parents of a proband

• All probands reported to date with PPP2R1A-NDD whose parents have undergone molecular genetic testing have the disorder as the result of a de novo PPP2R1A pathogenic variant.
• Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents:

• If the PPP2R1A 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].
• If a parent of the proband is known to have the PPP2R1A pathogenic variant identified in the proband, the risk to the sibs of inheriting the variant is 50%.

Offspring of a proband

• Each child of an individual with PPP2R1A-NDD has, in theory, a 50% chance of inheriting the PPP2R1A pathogenic variant.
• Individuals with PPP2R1A-related NDD are not yet known to reproduce, and it is unknown if pathogenic PPP2R1A variants affect fertility.

Other family members. Given that all probands with PPP2R1A-NDD reported to date have the disorder as a result of a de novo PPP2R1A pathogenic variant, the risk to other family members is presumed to be very 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 PPP2R1A 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 genetic testing may be considered.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

All known pathogenic variants causing PPP2R1A-related neurodevelopmental disorder (PPP2R1A-NDD) identified to date have been missense variants, predicting an amino acid change to the PPP2R1A protein. PPP2R1A encodes the scaffolding subunit (A-subunit) of protein phosphatase 2A (PP2A), the most important protein phosphatase in the human body. This scaffolding subunit connects the PP2A catalytic subunit (C-subunit) to one of the many regulatory B-subunits. B-subunit type determines substrate specificity, that is, which serine/threonine phosphate residues are targeted. Protein phosphorylation and dephosphorylation is the most important general mechanism for dynamic protein regulation in a cell, and phosphorylation of a given position is an equilibrium where various serine/threonine protein kinases (like cAMP-dependent protein kinase) and protein phosphatases (like PP2A) are important.

The most important B-subunit for brain function appears to be the PP2A B56-delta subunit PPP2R5D, and pathogenic missense variants in this gene are the cause of a phenotypically overlapping condition, PPP2R5D-related neurodevelopmental disorder. Remarkably, all pathogenic PPP2R1A variants retain binding to PPP2R5D [Lenaerts et al 2021]. This strongly suggests a dominant-negative type of gain-of-function effect. In theory, pathogenic PPP2R1A missense variants can block B56-delta-related substrates from being dephosphorylated, and also affect binding to other substrate-binding subunits (like B55-alpha) and inhibitory subunits (like CIP2A and SET) [Verbinnen et al 2021]. All the possible biochemical consequences of these scaffolding subunit changes have not been investigated, but a dominant-negative effect on protein dephosphorylation has been shown in prior studies [Houge et al 2015, Lenaerts et al 2021].

It should be noted that PPP2R1A loss-of-function changes (e.g., nonsense variants or deletions) are not known to cause PPP2R1A-NDD, even though the gene is quite intolerant to loss-of-function changes (gnomAD pLI is 0.98).

Mechanism of disease causation. Gain of function

Table 7.

Notable PPP2R1A Pathogenic Variants

Cancer and Benign Tumors

Even though many of the PPP2R1A missense variants described here are also found in tumor tissue (see COSMIC database), PPP2R1A-NDD is not known to be associated with an increased risk of cancer development.

Author Notes

The first author is an international expert in clinical dysmorphology with a specific interest in overgrowth syndromes. The second author is a biochemist and the foremost authority on PP2A dysfunction in both intellectual disability and cancer. The last author is a professor of medical genetics with extensive knowledge of clinical dysmorphology, genetic variant interpretation, and basic biochemistry. The latter two authors first described PPP2R1A-related neurodevelopmental disorder.

Revision History

• 12 May 2022 (ma) Review posted live
• 3 January 2022 (gh) Original submission

Literature Cited

• Barbosa S, Greville-Heygate S, Bonnet M, Godwin A, Fagotto-Kaufmann C, Kajava AV, Laouteouet D, Mawby R, Wai HA, Dingemans AJM, Hehir-Kwa J, Willems M, Capri Y, Mehta SG, Cox H, Goudie D, Vansenne F, Turnpenny P, Vincent M, Cogné B, Lesca G, Hertecant J, Rodriguez D, Keren B, Burglen L, Gérard M, Putoux A. C4RCD Research Group, Cantagrel V, Siquier-Pernet K, Rio M, Banka S, Sarkar A, Steeves M, Parker M, Clement E, Moutton S, Tran Mau-Them F, Piton A, de Vries BBA, Guille M, Debant A, Schmidt S, Baralle D. Opposite modulation of RAC1 by mutations in TRIO is associated with distinct, domain-specific neurodevelopmental disorders. Am J Hum Genet. 2020;106:338–55. [PMC free article: PMC7058823] [PubMed: 32109419]

• Burkardt DD, Tatton-Brown K, Dobyns W, Graham JM Jr. Approach to overgrowth syndromes in the genome era. Am J Med Genet C Semin Med Genet. 2019;181:483–90. [PubMed: 31793186]

• Houge G, Haesen D, Vissers LE, Mehta S, Parker MJ, Wright M, Vogt J, McKee S, Tolmie JL, Cordeiro N, Kleefstra T, Willemsen MH, Reijnders MR, Berland S, Hayman E, Lahat E, Brilstra EH, van Gassen KL, Zonneveld-Huijssoon E, de Bie CI, Hoischen A, Eichler EE, Holdhus R, Steen VM, Døskeland SO, Hurles ME, FitzPatrick DR, Janssens V. B56δ-related protein phosphatase 2A dysfunction identified in patients with intellectual disability. J Clin Invest. 2015;125:3051–62. [PMC free article: PMC4623570] [PubMed: 26168268]

• Lenaerts L, Reynhout S, Verbinnen I, Laumonnier F, Toutain A, Bonnet-Brilhault F, Hoorne Y, Joss S, Chassevent AK, Smith-Hicks C, Loeys B, Joset P, Steindl K, Rauch A, Mehta SG, Chung WK, Devriendt K, Holder SE, Jewett T, Baldwin LM, Wilson WG, Towner S, Srivastava S, Johnson HF, Daumer-Haas C, Baethmann M, Ruiz A, Gabau E, Jain V, Varghese V, Al-Beshri A, Fulton S, Wechsberg O, Orenstein N, Prescott K, Childs AM, Faivre L, Moutton S, Sullivan JA, Shashi V, Koudijs SM, Heijligers M, Kivuva E, McTague A, Male A, van Ierland Y, Plecko B, Maystadt I, Hamid R, Hannig VL, Houge G, Janssens V. The broad phenotypic spectrum of PPP2R1A-related neurodevelopmental disorders correlates with the degree of biochemical dysfunction. Genet Med. 2021;23:352–62. [PMC free article: PMC7862067] [PubMed: 33106617]

• Rahbari R, Wuster A, Lindsay SJ, Hardwick RJ, Alexandrov LB, Turki SA, Dominiczak A, Morris A, Porteous D, Smith B, Stratton MR, Hurles ME, et al. Timing, rates and spectra of human germline mutation. Nat Genet. 2016;48:126–33. [PMC free article: PMC4731925] [PubMed: 26656846]

• Reijnders MRF, Ansor NM, Kousi M, Yue WW, Tan PL, Clarkson K, Clayton-Smith J, Corning K, Jones JR, Lam WWK, Mancini GMS, Marcelis C, Mohammed S, Pfundt R, Roifman M, Cohn R, Chitayat D, Millard TH, Katsanis N, Brunner HG, Banka S, et al. RAC1 missense mutations in developmental disorders with diverse phenotypes. Am J Hum Genet. 2017;101:466–77. [PMC free article: PMC5591022] [PubMed: 28886345]

• Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–24. [PMC free article: PMC4544753] [PubMed: 25741868]

• Stenson PD, Mort M, Ball EV, Chapman M, Evans K, Azevedo L, Hayden M, Heywood S, Millar DS, Phillips AD, Cooper DN. The Human Gene Mutation Database (HGMD®): optimizing its use in a clinical diagnostic or research setting. Hum Genet. 2020;139:1197–207. [PMC free article: PMC7497289] [PubMed: 32596782]

• Tatton-Brown K, Loveday C, Yost S, Clarke M, Ramsay E, Zachariou A, Elliott A, Wylie H, Ardissone A, Rittinger O, Stewart F, Temple IK, Cole T., Childhood Overgrowth Collaboration. Mahamdallie S, Seal S, Ruark E, Rahman N. Mutations in epigenetic regulation genes are a major cause of overgrowth with intellectual disability. Am J Hum Genet. 2017;100:725–36. [PMC free article: PMC5420355] [PubMed: 28475857]

• Verbinnen I, Vaneynde P, Reynhout S, Lenaerts L, Derua R, Houge G, Janssens V. Protein Phosphatase 2A (PP2A) mutations in brain function, development, and neurologic disease. Biochem Soc Trans. 2021;49:1567–88. [PubMed: 34241636]

• Wallace A, Caruso P, Karaa A. A newborn with severe ventriculomegaly: expanding the PPP2R1A gene mutation phenotype. J Pediatr Genet. 2019;8:240–3. [PMC free article: PMC6824891] [PubMed: 31687265]

• Zhang Y, Li H, Wang H, Jia Z, Xi H, Mao X. A de novo variant identified in the PPP2R1A gene in an infant induces neurodevelopmental abnormalities. Neurosci Bull. 2020;36:179–82. [PMC free article: PMC6977796] [PubMed: 31531803]