Details of Disease

General Information of Disease (ID: DISEVUBA)

Disease Name Seckel syndrome
Synonyms Seckel-type Dwarfism; Harper's syndrome; SCKL; nanocephalic Dwarfism; bird-headed dwarfism; Virchow-Seckel dwarfism
Definition
A rare autosomal recessive inherited syndrome caused by mutations in the ATR gene, RBBP8 gene, CENPJ gene, CEP152 gene, CEP63 gene, NIN gene, DNA2 gene, or TRAIP gene. It is characterized by intrauterine growth retardation, dwarfism, microcephaly, mental retardation, and a "bird-headed" facial appearance.
Disease Hierarchy
DIS6SVEE: Syndromic disease
DISCPWH9: Autosomal recessive disease
DISEVUBA: Seckel syndrome
Disease Identifiers
MONDO ID
MONDO_0019342
UMLS CUI
C0265202
MedGen ID
78534
Orphanet ID
808
SNOMED CT ID
57917004

Molecular Interaction Atlas (MIA) of This Disease

Molecular Interaction Atlas (MIA)
This Disease Is Related to 13 DTT Molecule(s)
Gene Name DTT ID Evidence Level Mode of Inheritance REF
ATR TT8ZYBQ Supportive Autosomal recessive [1]
CENPE TTZD5QR Supportive Autosomal recessive [2]
PLK4 TTGPNZQ Supportive Autosomal recessive [3]
PNKP TTHR3IE moderate Genetic Variation [4]
ATR TT8ZYBQ Strong Genetic Variation [5]
CENPE TTZD5QR Strong Genetic Variation [2]
DNMT3A TTJUALD Strong Biomarker [6]
FANCA TTV5HJS Strong Biomarker [7]
GMNN TT390KA Strong Biomarker [8]
IGF1 TTT6LOU Strong Biomarker [9]
PLK4 TTGPNZQ Strong Biomarker [10]
PTPN11 TT7WUAV Strong Biomarker [11]
RAF1 TTAN5W2 Strong Biomarker [12]
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⏷ Show the Full List of 13 DTT(s)
This Disease Is Related to 28 DOT Molecule(s)
Gene Name DOT ID Evidence Level Mode of Inheritance REF
DNA2 OT4DJFFU Limited Genetic Variation [13]
NIN OTVH3M4Z Limited Genetic Variation [14]
ATR OTH0OP1J Supportive Autosomal recessive [1]
ATRIP OT78O9LF Supportive Autosomal recessive [15]
CENPE OTQ7AP04 Supportive Autosomal recessive [2]
CENPJ OTZCQZN5 Supportive Autosomal recessive [16]
CEP152 OTOKZR9B Supportive Autosomal recessive [17]
PLK4 OTV8KZDZ Supportive Autosomal recessive [3]
RBBP8 OTRHJ3GI Supportive Autosomal recessive [18]
TRAIP OTMPT9Y2 Supportive Autosomal recessive [19]
CD5L OTPY4WQR Strong Biomarker [16]
CDT1 OTVY53VG Strong Biomarker [20]
CENPF OT7AG0SW Strong Biomarker [21]
CEP135 OT1O9XYJ Strong Biomarker [22]
DONSON OTN5HE0W Strong Genetic Variation [23]
FAH OTGZA1YR Strong Biomarker [7]
LARP7 OTLLOZTL Strong Genetic Variation [24]
LIG4 OT40DNXU Strong Genetic Variation [25]
LZTR1 OTIDM6XO Strong Biomarker [26]
ORC1 OTHWU8IJ Strong Genetic Variation [27]
ORC4 OT3ACTST Strong Biomarker [20]
ORC6 OTKQN3KP Strong Biomarker [20]
PCNT OTW4Z65J Strong Biomarker [28]
RIT1 OTVNOGOH Strong Biomarker [29]
RTTN OT5PB986 Strong Genetic Variation [30]
SOS1 OTTCWXC3 Strong Biomarker [31]
TELO2 OT2YQ9L8 Strong Genetic Variation [32]
CDC6 OTX93FE7 Definitive Biomarker [33]
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⏷ Show the Full List of 28 DOT(s)

References

1 A splicing mutation affecting expression of ataxia-telangiectasia and Rad3-related protein (ATR) results in Seckel syndrome. Nat Genet. 2003 Apr;33(4):497-501. doi: 10.1038/ng1129. Epub 2003 Mar 17.
2 Mutations in CENPE define a novel kinetochore-centromeric mechanism for microcephalic primordial dwarfism. Hum Genet. 2014 Aug;133(8):1023-39. doi: 10.1007/s00439-014-1443-3. Epub 2014 Apr 20.
3 Mutations in PLK4, encoding a master regulator of centriole biogenesis, cause microcephaly, growth failure and retinopathy. Nat Genet. 2014 Dec;46(12):1283-1292. doi: 10.1038/ng.3122. Epub 2014 Oct 26.
4 Microcephalic primordial dwarfism in an Emirati patient with PNKP mutation.Am J Med Genet A. 2016 Aug;170(8):2127-32. doi: 10.1002/ajmg.a.37766. Epub 2016 May 27.
5 Analysis of novel missense ATR mutations reveals new splicing defects underlying Seckel syndrome.Hum Mutat. 2018 Dec;39(12):1847-1853. doi: 10.1002/humu.23648. Epub 2018 Sep 24.
6 The Tatton-Brown-Rahman Syndrome: A clinical study of 55 individuals with de novo constitutive DNMT3A variants.Wellcome Open Res. 2018 Apr 23;3:46. doi: 10.12688/wellcomeopenres.14430.1. eCollection 2018.
7 Normal expression of the Fanconi anemia proteins FAA and FAC and sensitivity to mitomycin C in two patients with Seckel syndrome.Am J Med Genet. 1999 Apr 23;83(5):388-91. doi: 10.1002/(sici)1096-8628(19990423)83:5<388::aid-ajmg9>3.0.co;2-1.
8 De Novo GMNN Mutations Cause Autosomal-Dominant Primordial Dwarfism Associated with Meier-Gorlin Syndrome. Am J Hum Genet. 2015 Dec 3;97(6):904-13. doi: 10.1016/j.ajhg.2015.11.006.
9 Intrauterine growth retardation and postnatal growth failure associated with deletion of the insulin-like growth factor I gene. N Engl J Med. 1996 Oct 31;335(18):1363-7. doi: 10.1056/NEJM199610313351805.
10 Analysis of centrosome and DNA damage response in PLK4 associated Seckel syndrome.Eur J Hum Genet. 2017 Oct;25(10):1118-1125. doi: 10.1038/ejhg.2017.120. Epub 2017 Aug 23.
11 Mouse model of Noonan syndrome reveals cell type- and gene dosage-dependent effects of Ptpn11 mutation.Nat Med. 2004 Aug;10(8):849-57. doi: 10.1038/nm1084. Epub 2004 Jul 25.
12 Increased BRAF heterodimerization is the common pathogenic mechanism for noonan syndrome-associated RAF1 mutants.Mol Cell Biol. 2012 Oct;32(19):3872-90. doi: 10.1128/MCB.00751-12. Epub 2012 Jul 23.
13 Biallelic variants in DNA2 cause microcephalic primordial dwarfism.Hum Mutat. 2019 Aug;40(8):1063-1070. doi: 10.1002/humu.23776. Epub 2019 Jun 23.
14 Identification of a Ninein (NIN) mutation in a family with spondyloepimetaphyseal dysplasia with joint laxity (leptodactylic type)-like phenotype.Matrix Biol. 2013 Oct-Nov;32(7-8):387-92. doi: 10.1016/j.matbio.2013.05.001. Epub 2013 May 9.
15 Identification of the first ATRIP-deficient patient and novel mutations in ATR define a clinical spectrum for ATR-ATRIP Seckel Syndrome. PLoS Genet. 2012;8(11):e1002945. doi: 10.1371/journal.pgen.1002945. Epub 2012 Nov 8.
16 Novel CENPJ mutation causes Seckel syndrome. J Med Genet. 2010 Jun;47(6):411-4. doi: 10.1136/jmg.2009.076646.
17 CEP152 is a genome maintenance protein disrupted in Seckel syndrome. Nat Genet. 2011 Jan;43(1):23-6. doi: 10.1038/ng.725. Epub 2010 Dec 5.
18 CtIP Mutations Cause Seckel and Jawad Syndromes. PLoS Genet. 2011 Oct;7(10):e1002310. doi: 10.1371/journal.pgen.1002310. Epub 2011 Oct 6.
19 TRAIP promotes DNA damage response during genome replication and is mutated in primordial dwarfism. Nat Genet. 2016 Jan;48(1):36-43. doi: 10.1038/ng.3451. Epub 2015 Nov 23.
20 Mutations in the pre-replication complex cause Meier-Gorlin syndrome. Nat Genet. 2011 Feb 27;43(4):356-9. doi: 10.1038/ng.775.
21 The kinetochore protein, CENPF, is mutated in human ciliopathy and microcephaly phenotypes. J Med Genet. 2015 Mar;52(3):147-56. doi: 10.1136/jmedgenet-2014-102691. Epub 2015 Jan 6.
22 Genomic and phenotypic delineation of congenital microcephaly. Genet Med. 2019 Mar;21(3):545-552. doi: 10.1038/s41436-018-0140-3. Epub 2018 Sep 14.
23 Microcephaly, short stature, and limb abnormality disorder due to novel autosomal biallelic DONSON mutations in two German siblings.Eur J Hum Genet. 2018 Sep;26(9):1282-1287. doi: 10.1038/s41431-018-0128-0. Epub 2018 May 14.
24 LARP7 variants and further delineation of the Alazami syndrome phenotypic spectrum among primordial dwarfisms: 2 sisters.Eur J Med Genet. 2019 Mar;62(3):161-166. doi: 10.1016/j.ejmg.2018.07.003. Epub 2018 Jul 10.
25 Mutations in the NHEJ component XRCC4 cause primordial dwarfism. Am J Hum Genet. 2015 Mar 5;96(3):412-24. doi: 10.1016/j.ajhg.2015.01.013. Epub 2015 Feb 26.
26 Mutations in LZTR1 drive human disease by dysregulating RAS ubiquitination.Science. 2018 Dec 7;362(6419):1177-1182. doi: 10.1126/science.aap7607. Epub 2018 Nov 15.
27 Mutations in ORC1, encoding the largest subunit of the origin recognition complex, cause microcephalic primordial dwarfism resembling Meier-Gorlin syndrome. Nat Genet. 2011 Feb 27;43(4):350-5. doi: 10.1038/ng.776.
28 Angelman syndrome protein UBE3A interacts with primary microcephaly protein ASPM, localizes to centrosomes and regulates chromosome segregation.PLoS One. 2011;6(5):e20397. doi: 10.1371/journal.pone.0020397. Epub 2011 May 25.
29 New Noonan syndrome model mice with RIT1 mutation exhibit cardiac hypertrophy and susceptibility to -adrenergic stimulation-induced cardiac fibrosis.EBioMedicine. 2019 Apr;42:43-53. doi: 10.1016/j.ebiom.2019.03.014. Epub 2019 Mar 18.
30 Expanding the phenotype of RTTN variations: a new family with primary microcephaly, severe growth failure, brain malformations and dermatitis.Clin Genet. 2016 Nov;90(5):445-450. doi: 10.1111/cge.12771. Epub 2016 Apr 29.
31 Activation of multiple signaling pathways causes developmental defects in mice with a Noonan syndromeassociated Sos1 mutation.J Clin Invest. 2010 Dec;120(12):4353-65. doi: 10.1172/JCI43910.
32 Novel compound heterozygous mutations in TELO2 in a patient with severe expression of You-Hoover-Fong syndrome.Mol Genet Genomic Med. 2017 Jul 28;5(5):580-584. doi: 10.1002/mgg3.287. eCollection 2017 Sep.
33 Meier-Gorlin syndrome genotype-phenotype studies: 35 individuals with pre-replication complex gene mutations and 10 without molecular diagnosis.Eur J Hum Genet. 2012 Jun;20(6):598-606. doi: 10.1038/ejhg.2011.269. Epub 2012 Feb 15.