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| Macrocephaly_Megalencephaly v0.143 | ZNRF3 |
Bryony Thompson gene: ZNRF3 was added gene: ZNRF3 was added to Macrocephaly_Megalencephaly. Sources: Literature Mode of inheritance for gene: ZNRF3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: ZNRF3 were set to 39168120 Phenotypes for gene: ZNRF3 were set to complex neurodevelopmental disorder MONDO:0100038 Review for gene: ZNRF3 was set to GREEN Added comment: 12 individuals with ZNRF3 variants and various phenotypes. 8 individuals with de novo missense and neurodevelopment disorders (NDD), including cluster of variants in the RING ligase domain with macrocephalic NDD. Plus 4 individuals from 3 families with de novo truncating or de novo/inherited large in-frame deletion variants with non-NDD phenotypes, including heart, adrenal, or nephrotic problems. Overall, 4 individuals had congenital heart defects and 2 had microcephaly. Also, supporting in vitro functional assays. Sources: Literature |
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| Macrocephaly_Megalencephaly v0.140 | TBC1D7 | Zornitza Stark edited their review of gene: TBC1D7: Added comment: PMID: 36669495 reports additional individuals with compound het variants identified via trio RNASeq.; Changed rating: GREEN; Changed publications: 24515783, 23687350, 36669495 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Macrocephaly_Megalencephaly v0.137 | MAX |
Rylee Peters gene: MAX was added gene: MAX was added to Macrocephaly_Megalencephaly. Sources: Literature Mode of inheritance for gene: MAX was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: MAX were set to 38141607 Phenotypes for gene: MAX were set to Syndromic disease (MONDO:0002254), MAX-related Review for gene: MAX was set to AMBER Added comment: Three individuals who each share a recurrent de novo germline variant in the MAX gene, resulting in a p.Arg60Gln substitution in the loop of the b-HLH-LZ domain. Affected individuals have a complex disorder consisting primarily of macrocephaly, polydactyly, and delayed ophthalmic development. Other phenotypes reported include intellectual disability, perianal abscesses, pectus carinatum, hypospadias, renal agenesis, single umbilical artery, flattened thoracic vertebrae. Functional analysis of the p.Arg60Gln variant shows a significant increase in CCND2 protein and a more efficient heterodimerization with c-Myc resulting in an increase in transcriptional activity of c-Myc. Sources: Literature |
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| Macrocephaly_Megalencephaly v0.136 | VCP |
Manny Jacobs gene: VCP was added gene: VCP was added to Macrocephaly_Megalencephaly. Sources: Literature Mode of inheritance for gene: VCP was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: VCP were set to PMID: 37883978 Phenotypes for gene: VCP were set to Neurodevelopmental disorder (MONDO: 0700092) Review for gene: VCP was set to GREEN Added comment: 13 unrelated individuals with childhood onset ID/DD disorder including macrocephaly, hypotonia and dysmorphic features. Non-specific / mild MRI findings. 12 de novo - 1 inherited Sources: Literature |
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| Macrocephaly_Megalencephaly v0.135 | PAK1 |
Lauren Rogers changed review comment from: PMID 37820543: 9/10 individuals had head circumferences at least greater than the 95th percentile in individuals with severe neurodevelopmental disorder Sources: Literature; to: PMID 37820543: 9/10 individuals had head circumferences at least greater than the 95th percentile in individuals with severe neurodevelopmental disorder. All missense variants Sources: Literature |
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| Macrocephaly_Megalencephaly v0.135 | PAK1 |
Lauren Rogers gene: PAK1 was added gene: PAK1 was added to Macrocephaly_Megalencephaly. Sources: Literature Mode of inheritance for gene: PAK1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: PAK1 were set to 37820543 Phenotypes for gene: PAK1 were set to Intellectual developmental disorder with macrocephaly, seizures, and speech delay (MIM#618158) Review for gene: PAK1 was set to GREEN Added comment: PMID 37820543: 9/10 individuals had head circumferences at least greater than the 95th percentile in individuals with severe neurodevelopmental disorder Sources: Literature |
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| Macrocephaly_Megalencephaly v0.132 | RAB5C |
Rylee Peters changed review comment from: 12 individuals with nine different heterozygous de novo variants in RAB5C. 9 with missense, 1 inframe duplication and 2 stop-gains (clinically more severe). All has mild-severe ID, 4/12 have epilepsy, 6/12 have macrocephaly (more than 3 SD). Sources: Literature; to: 12 individuals with nine different heterozygous de novo variants in RAB5C. 9 with missense, 1 inframe duplication and 2 stop-gains (clinically more severe). All have mild-severe ID, 4/12 have epilepsy, 6/12 have macrocephaly (more than 3 SD). Sources: Literature |
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| Macrocephaly_Megalencephaly v0.130 | RAB5C |
Rylee Peters gene: RAB5C was added gene: RAB5C was added to Macrocephaly_Megalencephaly. Sources: Literature Mode of inheritance for gene: RAB5C was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: RAB5C were set to PMID: 37552066 Phenotypes for gene: RAB5C were set to Neurodevelopmental disorder MONDO:0700092, RAB5C-related Penetrance for gene: RAB5C were set to Complete Review for gene: RAB5C was set to GREEN gene: RAB5C was marked as current diagnostic Added comment: 12 individuals with nine different heterozygous de novo variants in RAB5C. 9 with missense, 1 inframe duplication and 2 stop-gains (clinically more severe). All has mild-severe ID, 4/12 have epilepsy, 6/12 have macrocephaly (more than 3 SD). Sources: Literature |
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| Macrocephaly_Megalencephaly v0.128 | AXIN1 |
Elena Savva gene: AXIN1 was added gene: AXIN1 was added to Macrocephaly_Megalencephaly. Sources: Literature Mode of inheritance for gene: AXIN1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: AXIN1 were set to PMID: 37582359 Phenotypes for gene: AXIN1 were set to Syndromic disease, (MONDO:0002254), AXIN1-related Review for gene: AXIN1 was set to GREEN Added comment: PMID: 37582359 - four families (7 individuals) with three homozygous truncating variants. - all variant shown to result in reduced protein, though 1/3 would be NMD predicted - Probands had macrocephaly (4/6), GDD (3/7), hip dysplasia (5/6), cardiac anomalies eg. VSD/ASD (3/7), cranial hyperostosis and vertebral endplate sclerosis Sources: Literature |
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| Macrocephaly_Megalencephaly v0.115 | SLC30A7 |
Naomi Baker gene: SLC30A7 was added gene: SLC30A7 was added to Macrocephaly_Megalencephaly. Sources: Literature Mode of inheritance for gene: SLC30A7 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: SLC30A7 were set to PMID: 35751429 Phenotypes for gene: SLC30A7 were set to Joubert syndrome (MONDO:0018772), SLC30A7-related Review for gene: SLC30A7 was set to AMBER Added comment: PMID: 35751429: Two individuals reported with de novo variants, one missense and one delins resulting in missense. The first individual is a female with history of unilateral postaxial polydactyly, classic molar tooth sign on MRI, macrocephaly, ataxia, ocular motor apraxia, neurodevelopmental delay, and precocious puberty. The second individual had bilateral postaxial polydactyly, molar tooth sign, macrocephaly, developmental delay, and an extra oral frenulum. No functional studies reported. Sources: Literature |
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| Macrocephaly_Megalencephaly v0.114 | CTR9 |
Zornitza Stark gene: CTR9 was added gene: CTR9 was added to Macrocephaly_Megalencephaly. Sources: Literature Mode of inheritance for gene: CTR9 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: CTR9 were set to 35499524; 35717577 Phenotypes for gene: CTR9 were set to Neurodevelopmental disorder (MONDO:0700092), CTR9 related; Macrocephaly Review for gene: CTR9 was set to GREEN Added comment: Additional two individuals reported who had macrocephaly in addition to ID. Sources: Literature |
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| Macrocephaly_Megalencephaly v0.111 | ZDHHC9 |
Lucy Spencer gene: ZDHHC9 was added gene: ZDHHC9 was added to Macrocephaly_Megalencephaly. Sources: Literature Mode of inheritance for gene: ZDHHC9 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Publications for gene: ZDHHC9 were set to 29681091 Review for gene: ZDHHC9 was set to GREEN Added comment: Macrocephaly reported in at least 5 individuals with ZDHHC9 variants and related conditions Sources: Literature |
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| Macrocephaly_Megalencephaly v0.100 | ZBTB7A |
Daniel Flanagan gene: ZBTB7A was added gene: ZBTB7A was added to Macrocephaly_Megalencephaly. Sources: Expert list Mode of inheritance for gene: ZBTB7A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: ZBTB7A were set to 34515416; 31645653 Phenotypes for gene: ZBTB7A were set to Macrocephaly, neurodevelopmental delay, lymphoid hyperplasia, and persistent fetal hemoglobin (MIM#619769) Review for gene: ZBTB7A was set to GREEN Added comment: PMID: 34515416. Monoallelic ZBTB7A variants identified in 12 individuals from 11 families, with macrocephaly (11/12), some degree of ID (12/12), autistic features (7/12) and hypertrophy of pharyngeal lymphoid tissue (12/12). Variants included LoF variants and missense, 8 variants were de novo. PMID: 31645653. De novo ZBTB7A missense identified in a boy with macrocephaly, intellectual disability, and sleep apnea. Sources: Expert list |
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| Macrocephaly_Megalencephaly v0.98 | WDFY3 |
Ain Roesley gene: WDFY3 was added gene: WDFY3 was added to Macrocephaly_Megalencephaly. Sources: Literature Mode of inheritance for gene: WDFY3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: WDFY3 were set to 31327001 Phenotypes for gene: WDFY3 were set to Neurodevelopmental disorder with macrocephaly Penetrance for gene: WDFY3 were set to unknown Review for gene: WDFY3 was set to AMBER gene: WDFY3 was marked as current diagnostic Added comment: De novo (And 2x inherited from similarly affected parent) variants reported in individuals described to have macrocephaly, mostly PTCs and missense not in the PH domain (where microcephaly variants are reported) . But OFC doesn't sound very macro (5/9 >97th percentile and 4/9 between 87th and 95th percentiles). Het +/- mice displayed megalencephaly Sources: Literature |
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| Macrocephaly_Megalencephaly v0.92 | STT3A |
Elena Savva gene: STT3A was added gene: STT3A was added to Macrocephaly_Megalencephaly. Sources: Literature Mode of inheritance for gene: STT3A was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: STT3A were set to PMID: 34653363; 23842455; 30701557; 28424003 Phenotypes for gene: STT3A were set to Congenital disorder of glycosylation, type Iw MIM#615596 Mode of pathogenicity for gene: STT3A was set to Other Review for gene: STT3A was set to GREEN Added comment: ID/DD reported in all cases (at least 7 individuals from 3 unrelated families, with 2 different homozygous variants in STT3A) PMID: 34653363 - 16 patients from 9 families with new AD mode of inheritance (both de novo and inherited). All variants were missense within/around acritical active/catalytic sites. Patients aged 3-55yo, with children noted to be "healthy" until reaching young adulthood Clinical features include dysmorphic features, macrocephaly (6/16), mild-moderate ID/DD (10/16), short stature (8/16), skeletal abnormalities (10/16), muscle cramps (7/16). Functional studies verifies AR disease is caused by LOF variants, whereas the AD variants cause DN proven by cotransfection in WT yeast resulting in impaired glycosylation (protein levels unchanged). Sources: Literature |
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| Macrocephaly_Megalencephaly v0.71 | MYCN |
Kristin Rigbye gene: MYCN was added gene: MYCN was added to Macrocephaly_Megalencephaly. Sources: Literature Mode of inheritance for gene: MYCN was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: MYCN were set to 30573562 Phenotypes for gene: MYCN were set to Neurodevelopmental disorder with megalencephaly Mode of pathogenicity for gene: MYCN was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments Review for gene: MYCN was set to RED Added comment: Single report of a de novo missense p.T58M in an individual with a novel megalencephaly syndrome, a Japanese boy with an intellectual disability (ID), distinctive facies, megalencephaly, ventriculomegaly, hypoplastic corpus callosum, postnatal growth retardation, postaxial polydactyly and neuroblastoma. Biochemical and cell biology experiments revealed that the mutation renders MYCN resistant to proteolysis and may improperly potentiate cortical neuron proliferation. MYCN activity regulates granule neuron proliferation through induction of CCND1 and CCND2, and this syndrome was similar to CCND2 gene abnormalities that impart excessive protein stability cause megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome. This residue is also frequently mutated in c-Myc in Burkitt’s lymphoma (also due to GoF by gene amplification), consistent with its functions in cell proliferation and differentiation. Sources: Literature |
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| Macrocephaly_Megalencephaly v0.47 | MYT1L |
Natasha Brown gene: MYT1L was added gene: MYT1L was added to Macrocephaly_Megalencephaly. Sources: Literature Mode of inheritance for gene: MYT1L was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: MYT1L were set to (PMID: 32065501) Phenotypes for gene: MYT1L were set to intellectual disability; macrocephaly; epilepsy; autism Review for gene: MYT1L was set to GREEN Added comment: Over 50 individuals reported with deletions and SNVs affecting MYT1L, and variable phenotype comprising intellectual disability, obesity, and behavioral problems. 66% in a recent cohort had seizures. 13% had macrocephaly Sources: Literature |
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| Macrocephaly_Megalencephaly v0.0 | IDUA |
Zornitza Stark gene: IDUA was added gene: IDUA was added to Macrocephaly/Megalencephaly_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services Mode of inheritance for gene: IDUA was set to Unknown |
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