Table 6 PI3K-Akt-MTOR

Cappuccio et al., 2019 [264]

Severe presentation and complex brain malformations in an individual carrying a CCND2 variant

Federico II University, Naples, Italy

1 Subject, 2 Parents

-

Case study

Infantile spasms, siezures, developmental delay, bilateral PMG, white matter hypoplasia, fenestration of the septum pellucidum and hypoplasia of the anterior and posterior commissures, hippocampal hypoplasia and malrotation, hypoplastic thalami and lentiform nuclei malrotation of the vermis, brainstem hypoplasia

Bilateral postaxial polydactyly, patent foramen ovale and ductus arteriosus

-

TGS

NGS, sanger sequencing

De novo

12p13.32 (c.C839T, p.T280I in CCND2)

Jin et al., 2020 [10]

Exome sequencing implicates genetic disruption of prenatal neuro-gliogenesis in sporadic congenital hydrocephalus

The Rockefeller University, New York, NY, USA

381 Subjects, 1,798 Controls

-

Case–Control

Congenital hydrocephalus

-

Obstructive, Communicating

WES

CNV; sanger sequencing

De-novo

3q26.32 (PIK3CA mutations: p.D350N; p.E365K; p.G914R; p.R770Q; p.N345S); 10q23.31 (PTEN mutations: p.Y16X; p.R130Q; p.R335X; p.S305N); 1p36.22 (MTOR mutations: p.E1799K; p.M304T; p.R769C; p.R1161G; p.R1170C; p.H1782R); Mutations in 3p22.3 (TRIM71), 3p21.31 (SMARCC1), 17q25.1 (FOXJ1), 1q43 (FMN2), 9q22.32 (PTCH1) and 11q23.3 (FXYD2)

Maguolo et al., 2018 [265]

Clinical pitfalls in the diagnosis of segmental overgrowth syndromes: a child with the c.2740G > A mutation in PIK3CA gene

University Hospital of Verona, Verona, Italy

1 Subject

Italian

Case study

Cerebellar tonsillar ectopia, a markedly thick corpus callosum, and white matter abnormalities

Lateralized overgrowth (segmental overgrowth syndrome)

-

TGS

Targeted NGS

-

3q26.32 (c.G2740A, pG914R in exon 18 of PIK3CA)

Maini et al., 2018 [266]

A Novel CCND2 Mutation in a Previously Reported Case of Megalencephaly and Perisylvian Polymicrogyria with Postaxial Polydactyly and Hydrocephalus

Azienda Unità Sanitaria Locale, Arcispedale Santa Maria Nuova, IRCCS, Reggio Emilia, Italy

1 Subject, Controls used

-

Case study

Intellectual disability, seizures

Aphasia, postaxial polydactyly

-

WES

Sanger sequencing, direct sequencing

-

12p13.32 (c.C839T, p.T280I in CCND2)

McDermott et al., 2018 [267]

Hypoglycaemia represents a clinically significant manifestation of PIK3CA- and CCND2-associated segmental overgrowth

St Mary's Hospital, Central Manchester University Hospitals, NHS Foundation Trust Manchester Academic Health Sciences Centre, Manchester, UK

6 Subjects

-

Case series

Polymicrogyria

Polydactyly, capillary malformation, endocrine abnormalities

-

TGS

NGS; sanger sequencing

-

3q26.32 (PIK3CA mutations: c.G1048A, p.D350N; c.G2176A, p.E726K; c.G263A, p.R88Q); 12p13.32 (c.C841G, p.P281R in CCND2)

Mirzaa et al., 2015 [268]

Characterisation of mutations of the phosphoinositide-3-kinase regulatory subunit, PIK3R2, in perisylvian polymicrogyria: a next-generation sequencing study

University of Washington, Seattle, WA, USA; Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA, USA

20 Subjects, Controls used

USA

Case series

Polymicrogyria, seizures

Oromotor weakness

-

WES

AD assay; smMIPs; amplicon sequencing; sanger sequencing

De novo, maternal,

19p13.11 (c.G1117A, p.G373R and c. A1126G, p.K376E in PIK3R2)

Mirzaa, et al. 2013 [269]

Megalencephaly syndromes and activating mutations in the PI3K-AKT pathway: MPPH and MCAP

Center for Integrative Brain Research, University of Washington, Seattle Children's Research Institute, Seattle, WA, USA

50 Subjects

-

Case series

Cerebellar tonsillar ectopia or Chiari malformation, cortical brain abnormalities, macrocephaly

Postaxial polydactyly

-

WES

Sanger sequencing; REF; targeted ultra-deep sequencing

De novo

19p13.11 (p.G373R in PIK3R2); 1q43-q44 (p.R465W and p.N229S in AKT3); 3q26.32 (PIK3CA mutations: c.G241A, p.E81K; c.G263A, p.R88Q; c.G1090A, p.G364R; c.G1093A, p.E365K; c.G1133A, p.C378Y; c.1359_1361del, p.E453del; c.G1633A, p.E545K; c.G2176A, p.E726K; c.G2740A, p.G914R; c.A3062G, p.Y1021C; c.A3073G, p.T1025A; c.C3104T, p.A1035V; c.G3129T, p.M1043I; c.C3139T, p.H1047Y; c.G3145A, p.G1049S)

Ortega-Recalde et al., 2015 [270]

Biallelic HERC1 mutations in a syndromic form of overgrowth and intellectual disability

Escuela de Medicina y Ciencias de la Salud, Universidad del Rosario, Bogotá, Colombia

2 Subjects

Colombian

Case study

Intellectual disability

Overgrowth, kyphoscoliosis and facial dysmorphism

Communicating

WES

NGS, sanger sequencing

AR

15q22.31 (c.G2625A, p.W875X and c.G13559A, p.G4520E in HERC1)

Poduri et al., 2012 [271]

Somatic activation of AKT3 causes hemispheric developmental brain malformations

Children's Hospital Boston, 300 Longwood Avenue, Boston, MA 02115, USA

8 Subjects, Controls used

-

Case series

Intellectual disability and severe, intractable epilepsy

-

TGS

CNV; SNP; Karyotyping

De novo

1q43-q44 (c.G49A, p.E17K in AKT3)

Riviere et al., 2012 [272]

De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes

Seattle Children's Hospital, Seattle, Washington, USA

52 Subjects, 95 Controls

European

Case series

Megalocephaly, variable cortical malformation

Growth dysregulation with variable asymmetry, developmental vascular anomalies, distal limb malformations (syndactyly and polydactyly), and a mild connective tissue dysplasia

-

TES

Sanger sequencing; REF; targeted deep sequencing

De novo

1q43-q44 (c.C1393T, p.R465W and c.A686G, p.N229S in AKT3); 19p13.11 (c.G1117A; p.G373R in PIK3R2); 3q26.32 (PIK3CA mutations: c.G241A, p.E81K; c.G263A, p.R88Q; c.G1090A, p.G364R; c.G1093A, p.E365K; c.G1133A, p.C378Y; c.1359_1361del, p.E453del; c.G1633A, p.E545K; c.G2176A, p.E726K; c.G2740A, p.G914R; c.A3062G, p.Y1021C; c.A3073G, p.T1025A; c.C3104T, p.A1035V; c.G3129T, p.M1043I; c.C3139T, p.H1047Y; c.G3145A, p.G1049S)

Sameshima et al., 2019 [273]

MPPH syndrome with aortic coarctation and macrosomia due to CCND2 mutations

Hyogo Prefectural Awaji Medical Center, Sumoto, Hyogo, Japan

1 Subject, 2 Parents

Japanese

Case study

Polymicrogyria, seizures

Forehead protrusion, sacral cusp depression, low auricle, depressed nasal bridge and postaxial polydactyly, aortic coarctation

-

TGS

NGS, sanger sequencing

-

12p13.32 (c.C842G, p.P281R in CCND2)

Szalai et al., 2020 [274]

Maternal mosaicism underlies the inheritance of a rare germline AKT3 variant which is responsible for megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome in two Roma half-siblings

University of Pecs, Medical School, Department of Medical Genetics, Pecs, Hungary

2 Subjects

Hungarian Roma

Case study

Intellectual disability, epilepsy, brain malformations, and megalencephaly

Dysmorphic features, visual impairment

-

WES, cytogenetics

Karyotyping; aCGH; sanger sequencing

Maternal mosaicism

1q43-q44 (c.C1393T, p.R465W in AKT3)

Tapper et al., 2014 [275]

Megalencephaly syndromes: exome pipeline strategies for detecting low-level mosaic mutations

University of Southampton, Southampton, Hampshire, United Kingdom; Wessex Regional Genetics Laboratory, Salisbury District Hospital, Salisbury, Wiltshire, United Kingdom

3 Subjects, 4 Parents

-

Case series

Macrocephaly, dysmorphic cerebellum, hypotonia

Capillary malformations, overgrowth and asymmetry, developmental delay

-

WES, cytogenetics

aCGH; sanger sequencing

-

3q26.32 (c.G2176A, p.E726K in PIK3CA); 19p13.11 (c.G1117A, p.G373R in PIK3R2)

Tenorio et al., 2014 [276]

A new overgrowth syndrome is due to mutations in RNF125

Hospital Universitario La Paz, Universidad Autónoma de Madrid (UAM), Madrid, Spain

6 Subjects, 350 Control

Spanish

Case series

Macrocephaly, intellectual disability

Overgrowth, hypoglycemia, inflammatory diseases resembling sjögren syndrome

-

TGS, cytogenetics

Karyotyping; aCGH; SNP array; MLPA; high-resolution melting; sanger sequencing; pyrosequencing

De novo

18q12.1 (RNF125 mutations: c.G336A, p.M112I; c.C488T, p.S163L; c.C520T, p.R174C)

Terrone et al., 2016 [277]

De novo PIK3R2 variant causes polymicrogyria, corpus callosum hyperplasia and focal cortical dysplasia

Federico II University, Naples, Italy

1 Subject

Italian

Case study

Left spastic hemiplegia, megalencephaly, perisylvian polymicrogyria, and mega corpus callosum

Synophrys, depressed nasal bridge, anteverted nares, pectus excavatum, broad thumb and hallux

-

WES

Sanger sequencing

De novo

19p13.11 (c.G1669C, p.D557H in exon 13 of PIK3R2)

Zarate et al., 2019 [278]

Constitutive activation of the PI3K-AKT pathway and cardiovascular abnormalities in an individual with Kosaki overgrowth syndrome

University of Arkansas for Medical Sciences, Little Rock, Arkansas

1 Subject, 1 Control

-

Case study

Dandy-Walker malformation, cervical spine arachnoid cyst, progressive scoliosis, white matter lesions, spastic diplegia

Craniofacial dysmorphism, hyperextensible skin, cardiac saccular aneurysms, developmental delay, low-frequency hearing loss

Obstructive

TES

Exome sequencing trio analysis, sanger sequencing

De novo

5q32 (c.T1696C, p.W566R in exon 12 of PDGFRB)