Details of Disease

Disease Name

Megalencephaly

macroencephaly; megalencephaly (disease); megalencephaly

Definition

A congenital abnormality in which the occipitofrontal circumference is greater than two standard deviations above the mean for a given age. It is associated with hydrocephalus; subdural effusion; arachnoid cysts; or is part of a genetic condition (e.g., alexander disease; sotos syndrome).

Disease Hierarchy

DISQCXZX: Disorder of development or morphogenesis

DIS6ZC3X: Brain disease

DISYW5SV: Megalencephaly

Disease Identifiers

MONDO ID

MONDO_0016608

MESH ID

D058627

UMLS CUI

C0221355

MedGen ID

65141

HPO ID

HP:0001355

Orphanet ID

2477

SNOMED CT ID

12138000

General Information of Disease (ID: DISYW5SV)

Molecular Interaction Atlas (MIA) of This Disease

Molecular Interaction Atlas (MIA)

This Disease Is Related to 7 DTT Molecule(s)

Gene Name	DTT ID	Evidence Level	Mode of Inheritance	REF
AKT3	TTO6SGY	moderate	Genetic Variation	[1]
LRP5	TT7VMG4	moderate	Genetic Variation	[2]
CACNA1E	TTYRP0M	Strong	Biomarker	[3]
DNMT3A	TTJUALD	Strong	Biomarker	[4]
NSD1	TTTSJ3H	Strong	Genetic Variation	[5]
ODC1	TTUMGNO	Strong	Genetic Variation	[6]
THRA	TTTSEPU	Strong	Biomarker	[7]
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⏷ Show the Full List of 7 DTT(s)

This Disease Is Related to 52 DOT Molecule(s)

Gene Name	DOT ID	Evidence Level	Mode of Inheritance	REF
CDKL5	OTGL5HRV	Limited	Biomarker	[8]
CHD8	OTS7A6AF	Limited	Genetic Variation	[9]
CTDNEP1	OTK8LGAB	Limited	Biomarker	[10]
FOXG1	OTAW57J4	Limited	Biomarker	[11]
GABARAP	OTAQUX6E	Limited	Biomarker	[10]
GATAD2B	OTJL128N	Limited	Biomarker	[12]
HERC1	OT73FVYZ	Limited	Genetic Variation	[13]
KCTD13	OTSKZ1KM	Limited	Biomarker	[14]
KPTN	OTDWWFZJ	Limited	Genetic Variation	[15]
LINGO2	OT3N88Q1	Limited	Genetic Variation	[16]
PARVB	OT9OGVWX	Limited	Genetic Variation	[17]
PAX1	OT0Y3MIM	Limited	Biomarker	[18]
RHEB	OTFLTSEC	Limited	Genetic Variation	[19]
RIN2	OTCY73U9	Limited	Genetic Variation	[20]
STXBP1	OTRYA8C3	Limited	Biomarker	[21]
SULT4A1	OT7AL3KJ	Limited	Genetic Variation	[17]
NFIX	OT1DPZAE	Disputed	Genetic Variation	[22]
PIK3R2	OTZSUQK5	Disputed	Genetic Variation	[23]
ASXL2	OTNG4E2M	moderate	Biomarker	[24]
CRADD	OT02TZ4S	moderate	Genetic Variation	[25]
KIF7	OT1J6NAW	moderate	Genetic Variation	[26]
NFIB	OTX94PD0	moderate	Genetic Variation	[27]
OFD1	OTAZW5TK	moderate	Genetic Variation	[28]
PPP2R5D	OT43TTX0	moderate	Genetic Variation	[29]
PTCH1	OTMG07H5	moderate	Genetic Variation	[30]
RAB39B	OTDCLLT0	moderate	Genetic Variation	[31]
SOX9	OTVDJFGN	moderate	Genetic Variation	[32]
TBC1D7	OT1ALJ63	moderate	Genetic Variation	[33]
ASXL3	OTNDJWEZ	Strong	Biomarker	[24]
BRWD3	OT3BM9B0	Strong	Biomarker	[34]
CCND2	OTDULQF9	Strong	Biomarker	[35]
CHD3	OTDBU4F3	Strong	Genetic Variation	[36]
CHD4	OTBDEHDP	Strong	Genetic Variation	[12]
LEMD3	OTILAM4I	Strong	Genetic Variation	[37]
MAST1	OTEYFN5O	Strong	Genetic Variation	[38]
MLC1	OTCNZLSP	Strong	Biomarker	[39]
NCAM2	OT8LBJN8	Strong	Genetic Variation	[40]
NFIA	OTDHQ9CG	Strong	Genetic Variation	[41]
NOTCH2NLA	OTD5QPCI	Strong	Genetic Variation	[42]
NTM	OTHF0UQU	Strong	Genetic Variation	[43]
PAK3	OT80M3BV	Strong	Genetic Variation	[44]
PIGM	OTY98K40	Strong	Biomarker	[45]
POMK	OT36HLDO	Strong	Genetic Variation	[46]
PPP1CB	OTYFTYFR	Strong	Biomarker	[47]
RNASET2	OTWY64L7	Strong	Biomarker	[48]
RRAS2	OT83NCEB	Strong	Genetic Variation	[49]
SPRED1	OTKX7P8G	Strong	Genetic Variation	[50]
STK3	OTLNSCQD	Strong	Biomarker	[44]
STX16	OTM7TAOE	Strong	Genetic Variation	[51]
SUPT16H	OT9XWMQZ	Strong	Genetic Variation	[52]
SZT2	OTB4FVP4	Strong	Genetic Variation	[53]
TPTE	OT0JNP52	Strong	Biomarker	[54]
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⏷ Show the Full List of 52 DOT(s)

References

1	A novel de novo germline mutation Glu40Lys in AKT3 causes megalencephaly with growth hormone deficiency.Am J Med Genet A. 2017 Apr;173(4):1071-1076. doi: 10.1002/ajmg.a.38099. Epub 2017 Feb 12.
2	An autosomal dominant high bone mass phenotype in association with craniosynostosis in an extended family is caused by an LRP5 missense mutation. J Bone Miner Res. 2005 Jul;20(7):1254-60. doi: 10.1359/JBMR.050303. Epub 2005 Mar 7.
3	De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias. Am J Hum Genet. 2018 Nov 1;103(5):666-678. doi: 10.1016/j.ajhg.2018.09.006. Epub 2018 Oct 18.
4	Further delineation of neuropsychiatric findings in Tatton-Brown-Rahman syndrome due to disease-causing variants in DNMT3A: seven new patients.Eur J Hum Genet. 2020 Apr;28(4):469-479. doi: 10.1038/s41431-019-0485-3. Epub 2019 Nov 4.
5	The phenotypic spectrum of duplication 5q35.2-q35.3 encompassing NSD1: is it really a reversed Sotos syndrome?.Am J Med Genet A. 2013 Sep;161A(9):2158-66. doi: 10.1002/ajmg.a.36046. Epub 2013 Aug 2.
6	Gain-of-function variants in the ODC1 gene cause a syndromic neurodevelopmental disorder associated with macrocephaly, alopecia, dysmorphic features, and neuroimaging abnormalities.Am J Med Genet A. 2018 Dec;176(12):2554-2560. doi: 10.1002/ajmg.a.60677. Epub 2018 Nov 26.
7	Diverse Genotypes and Phenotypes of Three Novel Thyroid Hormone Receptor- Mutations.J Clin Endocrinol Metab. 2016 Aug;101(8):2945-54. doi: 10.1210/jc.2016-1404. Epub 2016 May 4.
8	Neurodevelopmental and neurobehavioral characteristics in males and females with CDKL5 duplications.Eur J Hum Genet. 2015 Jul;23(7):915-21. doi: 10.1038/ejhg.2014.217. Epub 2014 Oct 15.
9	Neurodevelopmental phenotype associated with CHD8-SUPT16H duplication.Neurogenetics. 2020 Jan;21(1):67-72. doi: 10.1007/s10048-019-00599-w. Epub 2019 Dec 10.
10	Neurodevelopmental delays and macrocephaly in 17p13.1 microduplication syndrome.Am J Med Genet A. 2014 Nov;164A(11):2887-91. doi: 10.1002/ajmg.a.36708. Epub 2014 Aug 13.
11	Snf2h Drives Chromatin Remodeling to Prime Upper Layer Cortical Neuron Development.Front Mol Neurosci. 2019 Oct 17;12:243. doi: 10.3389/fnmol.2019.00243. eCollection 2019.
12	The NuRD complex and macrocephaly associated neurodevelopmental disorders.Am J Med Genet C Semin Med Genet. 2019 Dec;181(4):548-556. doi: 10.1002/ajmg.c.31752. Epub 2019 Nov 18.
13	A nonsense variant in HERC1 is associated with intellectual disability, megalencephaly, thick corpus callosum and cerebellar atrophy.Eur J Hum Genet. 2016 Mar;24(3):455-8. doi: 10.1038/ejhg.2015.140. Epub 2015 Jul 8.
14	CRISPR/Cas9-mediated Knockout of the Neuropsychiatric Risk Gene KCTD13 Causes Developmental Deficits in Human Cortical Neurons Derived from Induced Pluripotent Stem Cells.Mol Neurobiol. 2020 Feb;57(2):616-634. doi: 10.1007/s12035-019-01727-1. Epub 2019 Aug 11.
15	Novel homozygous mutation in KPTN gene causing a familial intellectual disability-macrocephaly syndrome.Am J Med Genet A. 2015 Aug;167A(8):1913-5. doi: 10.1002/ajmg.a.37105. Epub 2015 Apr 5.
16	Haploinsufficiency of the miR-873/miR-876 microRNA cluster is associated with craniofacial abnormalities.Gene. 2015 Apr 25;561(1):95-100. doi: 10.1016/j.gene.2015.02.018. Epub 2015 Feb 11.
17	Interstitial 22q13 deletions not involving SHANK3 gene: a new contiguous gene syndrome.Am J Med Genet A. 2014 Jul;164A(7):1666-76. doi: 10.1002/ajmg.a.36513. Epub 2014 Apr 3.
18	Macrocephaly, epilepsy, autism, dysmorphic features, and mental retardation in two sisters: a new autosomal recessive syndrome?.J Med Genet. 1997 Oct;34(10):849-51. doi: 10.1136/jmg.34.10.849.
19	Variation in a range of mTOR-related genes associates with intracranial volume and intellectual disability.Nat Commun. 2017 Oct 20;8(1):1052. doi: 10.1038/s41467-017-00933-6.
20	Leukoencephalopathy in RIN2 syndrome: Novel mutation and expansion of clinical spectrum.Eur J Med Genet. 2020 Jan;63(1):103629. doi: 10.1016/j.ejmg.2019.02.002. Epub 2019 Feb 13.
21	Familial 9q33q34 microduplication in siblings with developmental disorders and macrocephaly.Eur J Med Genet. 2017 Dec;60(12):650-654. doi: 10.1016/j.ejmg.2017.08.017. Epub 2017 Sep 9.
22	19p13 microduplications encompassing NFIX are responsible for intellectual disability, short stature and small head circumference.Eur J Hum Genet. 2018 Jan;26(1):85-93. doi: 10.1038/s41431-017-0037-7. Epub 2017 Nov 28.
23	De novo PIK3R2 variant causes polymicrogyria, corpus callosum hyperplasia and focal cortical dysplasia.Eur J Hum Genet. 2016 Aug;24(9):1359-62. doi: 10.1038/ejhg.2016.7. Epub 2016 Feb 10.
24	De Novo Truncating Variants in ASXL2 Are Associated with a Unique and Recognizable Clinical Phenotype. Am J Hum Genet. 2016 Oct 6;99(4):991-999. doi: 10.1016/j.ajhg.2016.08.017. Epub 2016 Sep 29.
25	Mutations in CRADD Result in Reduced Caspase-2-Mediated Neuronal Apoptosis and Cause Megalencephaly with a Rare Lissencephaly Variant. Am J Hum Genet. 2016 Nov 3;99(5):1117-1129. doi: 10.1016/j.ajhg.2016.09.010. Epub 2016 Oct 20.
26	A mutation in KIF7 is responsible for the autosomal recessive syndrome of macrocephaly, multiple epiphyseal dysplasia and distinctive facial appearance. Orphanet J Rare Dis. 2012 May 15;7:27. doi: 10.1186/1750-1172-7-27.
27	NFIB Haploinsufficiency Is Associated with Intellectual Disability and Macrocephaly. Am J Hum Genet. 2018 Nov 1;103(5):752-768. doi: 10.1016/j.ajhg.2018.10.006.
28	A novel X-linked recessive mental retardation syndrome comprising macrocephaly and ciliary dysfunction is allelic to oral-facial-digital type I syndrome. Hum Genet. 2006 Sep;120(2):171-8. doi: 10.1007/s00439-006-0210-5. Epub 2006 Jun 17.
29	De novo missense variants in PPP2R5D are associated with intellectual disability, macrocephaly, hypotonia, and autism. Neurogenetics. 2016 Jan;17(1):43-9. doi: 10.1007/s10048-015-0466-9. Epub 2015 Nov 17.
30	Co-occurrence of mutations in FOXP1 and PTCH1 in a girl with extreme megalencephaly, callosal dysgenesis and profound intellectual disability.J Hum Genet. 2018 Nov;63(11):1189-1193. doi: 10.1038/s10038-018-0508-x. Epub 2018 Sep 4.
31	Mutations in the small GTPase gene RAB39B are responsible for X-linked mental retardation associated with autism, epilepsy, and macrocephaly. Am J Hum Genet. 2010 Feb 12;86(2):185-95. doi: 10.1016/j.ajhg.2010.01.011.
32	The presence of diminished white matter and corpus callosal thinning in a case with a SOX9 mutation.Brain Dev. 2018 Apr;40(4):325-329. doi: 10.1016/j.braindev.2017.09.002. Epub 2017 Sep 28.
33	TBC1D7 mutations are associated with intellectual disability, macrocrania, patellar dislocation, and celiac disease.Hum Mutat. 2014 Apr;35(4):447-51. doi: 10.1002/humu.22529.
34	Null variants and deletions in BRWD3 cause an X-linked syndrome of mild-moderate intellectual disability, macrocephaly, and obesity: A series of 17 patients.Am J Med Genet C Semin Med Genet. 2019 Dec;181(4):638-643. doi: 10.1002/ajmg.c.31750. Epub 2019 Nov 12.
35	A Novel CCND2 Mutation in a Previously Reported Case of Megalencephaly and Perisylvian Polymicrogyria with Postaxial Polydactyly and Hydrocephalus.Neuropediatrics. 2018 Jun;49(3):222-224. doi: 10.1055/s-0038-1641722. Epub 2018 Apr 11.
36	Author Correction: CHD3 helicase domain mutations cause a neurodevelopmental syndrome with macrocephaly and impaired speech and language.Nat Commun. 2019 Feb 15;10(1):883. doi: 10.1038/s41467-019-08800-2.
37	Mutations of the fibroblast growth factor receptor-3 gene in achondroplasia.Horm Res. 1996;45(1-2):108-10. doi: 10.1159/000184768.
38	Mutations in MAST1 Cause Mega-Corpus-Callosum Syndrome with Cerebellar Hypoplasia and Cortical Malformations. Neuron. 2018 Dec 19;100(6):1354-1368.e5. doi: 10.1016/j.neuron.2018.10.044. Epub 2018 Nov 15.
39	Megalencephalic leukoencephalopathy with cysts: the Glialcam-null mouse model.Ann Clin Transl Neurol. 2017 Jun 6;4(7):450-465. doi: 10.1002/acn3.405. eCollection 2017 Jul.
40	NCAM2 deletion in a boy with macrocephaly and autism: Cause, association or predisposition?.Eur J Med Genet. 2016 Oct;59(10):493-8. doi: 10.1016/j.ejmg.2016.08.006. Epub 2016 Sep 2.
41	A novel 1p31.3p32.2 deletion involving the NFIA gene detected by array CGH in a patient with macrocephaly and hypoplasia of the corpus callosum.Eur J Pediatr. 2010 Apr;169(4):463-8. doi: 10.1007/s00431-009-1057-2. Epub 2009 Sep 8.
42	Human-Specific NOTCH2NL Genes Affect Notch Signaling and Cortical Neurogenesis.Cell. 2018 May 31;173(6):1356-1369.e22. doi: 10.1016/j.cell.2018.03.051. Epub 2018 May 31.
43	11q24.2-25 micro-rearrangements in autism spectrum disorders: Relation to brain structures.Am J Med Genet A. 2015 Dec;167A(12):3019-30. doi: 10.1002/ajmg.a.37345. Epub 2015 Sep 3.
44	A de novo mutation in the X-linked PAK3 gene is the underlying cause of intellectual disability and macrocephaly in monozygotic twins.Eur J Med Genet. 2017 Apr;60(4):212-216. doi: 10.1016/j.ejmg.2017.01.004. Epub 2017 Jan 24.
45	Cerebral and portal vein thrombosis, macrocephaly and atypical absence seizures in Glycosylphosphatidyl inositol deficiency due to a PIGM promoter mutation. Mol Genet Metab. 2019 Sep-Oct;128(1-2):151-161. doi: 10.1016/j.ymgme.2019.08.003. Epub 2019 Aug 14.
46	Pathogenic homozygous variant in POMK gene is the cause of prenatally detected severe ventriculomegaly in two Lithuanian families.Am J Med Genet A. 2020 Mar;182(3):536-542. doi: 10.1002/ajmg.a.61453. Epub 2019 Dec 12.
47	Cleft palate and hypopituitarism in a patient with Noonan-like syndrome with loose anagen hair-1.Am J Med Genet A. 2018 Sep;176(9):2024-2027. doi: 10.1002/ajmg.a.40432. Epub 2018 Sep 21.
48	RNASET2-deficient leukoencephalopathy mimicking congenital CMV infection and Aicardi-Goutieres syndrome: a case report with a novel pathogenic variant.Orphanet J Rare Dis. 2019 Jul 26;14(1):184. doi: 10.1186/s13023-019-1155-9.
49	Germline-Activating RRAS2 Mutations Cause Noonan Syndrome. Am J Hum Genet. 2019 Jun 6;104(6):1233-1240. doi: 10.1016/j.ajhg.2019.04.014. Epub 2019 May 23.
50	Interaction between a Domain of the Negative Regulator of the Ras-ERK Pathway, SPRED1 Protein, and the GTPase-activating Protein-related Domain of Neurofibromin Is Implicated in Legius Syndrome and Neurofibromatosis Type 1.J Biol Chem. 2016 Feb 12;291(7):3124-34. doi: 10.1074/jbc.M115.703710. Epub 2015 Dec 3.
51	Macrosomia, obesity, and macrocephaly as first clinical presentation of PHP1b caused by STX16 deletion.Am J Med Genet A. 2016 Sep;170(9):2431-5. doi: 10.1002/ajmg.a.37818. Epub 2016 Jun 23.
52	Novel 14q11.2 microduplication including the CHD8 and SUPT16H genes associated with developmental delay. Am J Med Genet A. 2016 May;170A(5):1325-9. doi: 10.1002/ajmg.a.37579. Epub 2016 Feb 2.
53	Compound heterozygous SZT2 mutations in two siblings with early-onset epilepsy, intellectual disability and macrocephaly.Seizure. 2019 Mar;66:81-85. doi: 10.1016/j.seizure.2018.12.021. Epub 2018 Dec 23.
54	Reciprocal Relationship between Head Size, an Autism Endophenotype, and Gene Dosage at 19p13.12 Points to AKAP8 and AKAP8L.PLoS One. 2015 Jun 15;10(6):e0129270. doi: 10.1371/journal.pone.0129270. eCollection 2015.