Identification of mutations in the PI3K-AKT-mTOR signalling pathway in patients with macrocephaly and developmental delay and/or autism

Yeung, Kit San; Tso, Winnie W. Y.; Ip, Janice; Mak, Christopher Chun Yu; Leung, Gordon; Tsang, Mandy Ho Yin; Ying, Dingge; Pei, Steven L. C.; Lee, So Lun; Yang, Wanling; Chung, Brian Hon‐Yin

doi:10.1186/s13229-017-0182-4

Cited by 99 publications

(90 citation statements)

References 59 publications

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“…Protein Phosphatase 2 Regulatory Subunit B Delta (PPP2R5D)-related intellectual disability (ID) and neurodevelopmental delay is a disorder that mainly occurs due to de novo mutations in the PPP2R5D gene [1][2][3][4]. The PPP2R5D gene codes for one of the isoforms of the regulatory subunit family B56, of the heteromeric enzyme protein phosphatase 2A (PP2A) [5].…”

Section: Introductionmentioning

confidence: 99%

“…The PPP2R5D gene codes for one of the isoforms of the regulatory subunit family B56, of the heteromeric enzyme protein phosphatase 2A (PP2A) [5]. Mutations in PPP2R5D are associated with neurodevelopmental delay, autism spectrum disorder (ASD), ID, behavioral challenges, and so forth, which are seen soon after birth [1][2][3][4]6]. In the United States, this disorder is currently referred to as Jordan's syndrome, named after Jordan Lang, the first child diagnosed in the United States [7].…”

Section: Introductionmentioning

confidence: 99%

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PPP2R5D-Related Intellectual Disability and Neurodevelopmental Delay: A Review of the Current Understanding of the Genetics and Biochemical Basis of the Disorder

Biswas

Cary

Nolta

2020

IJMS

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Protein Phosphatase 2 Regulatory Subunit B′ Delta (PPP2R5D)-related intellectual disability (ID) and neurodevelopmental delay results from germline de novo mutations in the PPP2R5D gene. This gene encodes the protein PPP2R5D (also known as the B56 delta subunit), which is an isoform of the subunit family B56 of the enzyme serine/threonine-protein phosphatase 2A (PP2A). Clinical signs include intellectual disability (ID); autism spectrum disorder (ASD); epilepsy; speech problems; behavioral challenges; and ophthalmologic, skeletal, endocrine, cardiac, and genital malformations. The association of defective PP2A activity in the brain with a wide range of severity of ID, along with its role in ASD, Alzheimer’s disease, and Parkinson’s-like symptoms, have recently generated the impetus for further research into mutations within this gene. PP2A, together with protein phosphatase 1 (PP1), accounts for more than 90% of all phospho-serine/threonine dephosphorylations in different tissues. The specificity for a wide variety of substrates is determined through nearly 100 different PP2A holoenzymes that are formed by at least 23 types of regulatory B subunits, and two isoforms each of the catalytic subunit C and the structural subunit A. In the mammalian brain, PP2A-mediated protein dephosphorylation plays an important role in learning and memory. The PPP2R5D subunit is highly expressed in the brain and the PPP2A–PPP2R5D holoenzyme plays an important role in maintaining neurons and regulating neuronal signaling. From 2015 to 2017, 25 individuals with PPP2R5D-related developmental disorder were diagnosed. Since then, Whole-Exome Sequencing (WES) has helped to identify more unrelated individuals clinically diagnosed with a neurodevelopmental disorder with pathological variants of PPP2R5D. In this review, we discuss the current understanding of the clinical and genetic aspects of the disorder in the context of the known functions of the PP2A–PPP2R5D holoenzyme in the brain, as well as the pathogenic mutations in PPP2R5D that lead to deficient PP2A–PPP2R5D dephosphorylation and their implications during development and in the etiology of autism, Parkinson’s disease, Alzheimer’s disease, and so forth. In the future, tools such as transgenic animals carrying pathogenic PPP2R5D mutations, and patient-derived induced pluripotent stem cell lines need to be developed in order to fully understand the effects of these mutations on different neural cell types.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

PPP2R5D-Related Intellectual Disability and Neurodevelopmental Delay: A Review of the Current Understanding of the Genetics and Biochemical Basis of the Disorder

Biswas

Cary

Nolta

2020

IJMS

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“…The primary aim is to identify somatic mutations for genetic overgrowth syndrome. 14 Detailed classification was listed in Table S3.…”

Section: Clinical Diagnosismentioning

confidence: 99%

“…If the clinical geneticist was suspicious of somatic mosaicism in the subject, 13,14 buccal mucosa was also obtained as a germline source of DNA. If the clinical geneticist was suspicious of somatic mosaicism in the subject, 13,14 buccal mucosa was also obtained as a germline source of DNA.…”

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confidence: 99%

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Exome sequencing identifies molecular diagnosis in children with drug‐resistant epilepsy

Tsang

Leung

et al. 2018

Epilepsia Open

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Summary Objective Early onset drug‐resistant epilepsy is a neurologic disorder in which 2 antiepileptic drugs fail to maintain the seizure‐free status of the patient. Heterogeneous clinical presentations make the diagnosis challenging. We aim to identify the underlying genetic causes of a pediatric cohort with drug‐resistant epilepsy and evaluate whether the findings can provide information on patient management. Methods We include patients with drug‐resistant epilepsy onset before 18 years of age. Singleton clinical chromosomal microarray (CMA) followed by whole exome sequencing (WES) was performed using genomic DNA. In the first‐tier analysis of the exome data, we aimed to identify disease‐causing mutations in 546 genes known to cause, or to be associated with, epilepsy. For negative cases, we proceeded to exome‐wide analysis. Rare coding variants were interrogated for pathogenicity based on the American College of Medical Genetics and Genomics (ACMG) guidelines. Results We recruited 50 patients. We identified 6 pathogenic or likely pathogenic mutations, giving a diagnostic yield of 12%. Mutations were found in 6 different genes: SCN8A, SCN1A, MECP2, CDKL5, DEPDC5, and CHD2. The CDKL5 variant was found to be mosaic. One variant of unknown significance (VUS) in KCNT1 was found in a patient with compatible clinical features. Of note, a reported pathogenic SCN5A mutation known to contribute to Brugada syndrome, was also found in the patient with an SCN1A mutation. Significance Our study suggests that singleton WES is an effective diagnostic tool for drug‐resistant epilepsy. Genetic diagnosis can help to consolidate the clinical diagnosis, to facilitate phenotypic expansion, and to influence treatment and management options for seizure control in our patients. In our study, a significant portion of the genetic findings are known to be associated with an increased risk of sudden unexpected death in epilepsy (SUDEP). These findings could assist with more appropriate management in patients with epilepsy.

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An in‐frame deletion affecting the critical acid loop of PPP2R5D is associated with a neonatal lethal form of PPP2R5D‐related neurodevelopmental disorder

Alhajaj

Lacroix

Trakadis

et al. 2023

American J of Med Genetics Pt A

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Heterozygous pathogenic variants in PPP2R5D gene are associated with PPP2R5D‐related neurodevelopmental disorder, a rare autosomal dominant condition, characterized by neurodevelopmental impairment in childhood, macrocephaly/megalencephaly, hypotonia, epilepsy, and dysmorphic features. Up‐to‐date, only approximately 100 cases have been published in the literature and the full phenotypic and genotypic spectrum have not yet been fully described. PPP2R5D gene encodes the B56δ subunit of the PP2A enzyme complex. We describe a neonatal form of PPP2R5D‐related disorder with early infantile death, caused by a novel in‐frame deletion causing loss of 8 amino acids and insertion of serine at position 201 (p.Phe194_Pro201delinsSer) of the B56δ subunit. This deletion is predicted to disrupt a critical acidic loop of amino acids important for binding other subunits of the PP2A enzyme complex, and harbors many of the residues previously reported to cause a mild–moderate form of this condition. This report describes a neonatal lethal presentation of the PPP2R5D‐related neurodevelopmental disorder and provides additional evidence that disruption of the acidic loop is an important pathomechanism underlying PPP2R5D‐related disorder.

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Identification of mutations in the PI3K-AKT-mTOR signalling pathway in patients with macrocephaly and developmental delay and/or autism

Cited by 99 publications

References 59 publications

PPP2R5D-Related Intellectual Disability and Neurodevelopmental Delay: A Review of the Current Understanding of the Genetics and Biochemical Basis of the Disorder

PPP2R5D-Related Intellectual Disability and Neurodevelopmental Delay: A Review of the Current Understanding of the Genetics and Biochemical Basis of the Disorder

Exome sequencing identifies molecular diagnosis in children with drug‐resistant epilepsy

An in‐frame deletion affecting the critical acid loop of PPP2R5D is associated with a neonatal lethal form of PPP2R5D‐related neurodevelopmental disorder

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