Microcephaly Panel - Clinical Genetic Test - GTR

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Microcephaly Panel

Clinical Genetic Test

offered by

Genetic Services Laboratory

View lab's test page

GTR Test Accession: GTR000507771.10

CAP

INHERITED DISEASENERVOUS SYSTEMDYSMORPHOLOGY ... View more

Last updated in GTR: 2021-01-20

Last annual review date for the lab: 2024-07-22

At a Glance

Test purpose:

Diagnosis; Monitoring; Mutation Confirmation; ...

Conditions (72):

Periventricular heterotopia with microcephaly, autosomal recessive; Acquired hemoglobin H disease; Alpha thalassemia-X-linked intellectual disability syndrome more...

Genes (133):

ADARB1 (21q22.3); AFG2A (4q28.1); AGMO (7p21.2); AMPD2 (1p13.3); ANKLE2 (12q24.33) more...

Methods (2):

Molecular Genetics - Deletion/duplication analysis: Next-Generation (NGS)/Massively parallel sequencing (MPS); ...

Target population:

The target population for this test is patients suspected of …

Clinical validity:

Missense and frameshift mutations were identified in two Turkish families …

Clinical utility:

Establish or confirm diagnosis

Ordering Information

Offered by:

Genetic Services Laboratory
View lab's website
View lab's test page

Specimen Source:

Isolated DNA
Peripheral (whole) blood
Saliva
View specimen requirements

Who can order:

Genetic Counselor
Health Care Provider
Licensed Physician
Nurse Practitioner
Physician Assistant
Registered Nurse

CPT codes:

81443

**AMA CPT codes notice

Contact Policy:

Laboratory can only accept contact from health care providers. Patients/families are encouraged to discuss genetic testing options with their health care provider.

How to Order:

All samples should be shipped via overnight delivery at room temperature.
No weekend or holiday deliveries.
Label each specimen with the patient’s name, date of birth and date sample collected.
Send specimens with complete requisition and consent form, otherwise, specimen processing may be delayed.
Order URL

Test service:

Clinical Testing/Confirmation of Mutations Identified Previously
Confirmation of research findings

Test additional service:

Custom Prenatal Testing
Custom mutation-specific/Carrier testing

Test development:

Test developed by laboratory but exempt from FDA oversight (eg. NYS CLEP approved, offered within a hospital or clinic)

Informed consent required:

Pre-test genetic counseling required:

Decline to answer

Post-test genetic counseling required:

Decline to answer

Recommended fields not provided:

Test Order Code, Lab contact for this test, Test strategy

Conditions

Total conditions: 72

Condition/Phenotype	Identifier

Test Targets

Genes

Total genes: 133

Gene	Associated Condition	Germline or Somatic	Allele (Lab-provided)	Variant in NCBI

Methodology

Total methods: 2

Method Category

Test method

Instrument *

Deletion/duplication analysis

Next-Generation (NGS)/Massively parallel sequencing (MPS)

Sequence analysis of the entire coding region

Next-Generation (NGS)/Massively parallel sequencing (MPS)

* Instrument: Not provided

Clinical Information

Test purpose:

Diagnosis; Monitoring; Mutation Confirmation; Pre-symptomatic; Risk Assessment; Screening

Clinical validity:

Missense and frameshift mutations were identified in two Turkish families with autosomal recessive periventricular heterotopia with microcephaly [OMIM#608097] which is characterized by microcephaly, periventricular heterotopia, intellectual disability and recurrent infections. A homozygous mutation in ATR was been identified in two consanguineous Pakistani families with Seckel syndrome [OMIM#210600]. Seckel syndrome is … Missense and frameshift mutations were identified in two Turkish families with autosomal recessive periventricular heterotopia with microcephaly [OMIM#608097] which is characterized by microcephaly, periventricular heterotopia, intellectual disability and recurrent infections. A homozygous mutation in ATR was been identified in two consanguineous Pakistani families with Seckel syndrome [OMIM#210600]. Seckel syndrome is characterized by severe proportionally short stature with severe microcephaly, a ‘bird like’ profile including a beak-like protusion of the nose, narrow face, receding lower jaw and micrognathia, and intellectual disability. Mutations in ATRX are associated with a wide and clinically heterogeneous spectrum of X-linked mental retardation syndromes. Clinical features may include intellectual disability, hypotonia, microcephaly, genital abnormalities, short stature and seizures. Affected individuals may have microcytic hypochromic anemia characteristic of alpha-thalassemia, however many do not. Carrier females are typically not affected. X-linked mental retardation and microcephaly with pontine and cerebellar hypoplasia (MIC-PHC) [OMIM #300749] is associated with de novo CASK mutations, and is characterized by severe or profound intellectual disability, microcephaly, and disproportionate pontine and cerebellar hypoplasia in females. Mutations associated with MIC-PHC are believed to be lethal in males, however milder familial mutations may also be observed, which can cause intellectual disability in males. A homozygous nonsense mutation was identified in CEP63 in a consanguineous family of Pakistani descent with three members with primary microcephaly and proportionate short stature, clinically consistent with mild Seckel syndrome [OMIM#614728]. A homozygous missense mutation was identified in 5 infants from 4 Jewish families with postnatal progressive microcephaly and severe developmental retardation associated with cerebral and cerebellar atrophy. Mutations in NDE1 have been reported in children with severe congenital microcephaly, with brains smaller than 10 SD below the mean, simplified gyri, and profound intellectual disability. Homozygous mutations have been reported in one Turkish, two Saudi and two Pakistani consanguineous families. Mutations in PCNT have been identified in patients with microcephalic osteodysplastic primordial dwarfism type II (MOPD II) [OMIM#210720]. MOPD II is characterized by intrauterine growth retardation, severe proportionate short stature, and microcephaly. Rauch et al. (2008) identified 29 different homozygous or compound heterozygous mutations in the PCNT gene in 25 patients with MOPD2. Mutations in the PNKP gene have been described in seven families with autosomal recessive microcephaly, infantile-onset seizures, and developmental delay (MCSZ) [OMIM#613402]. Both homozygous and compound heterozygous mutations have been reported. In patients with MCSZ, intellectual disability is usually severe to profound with variable behavioral problems and severe and intractable seizures. A homozygous splicing mutation in RBBP8 was identified in four siblings affected by Seckel syndrome [OMIM#606744] in a consanguinous Iraqi family. Seckel syndrome is characterized by severe proportionally short stature with severe microcephaly, a ‘bird like’ profile including a beak-like protusion of the nose, narrow face, receding lower jaw and micrognathia, and intellectual disability. Amish lethal microcephaly [OMIM#607196] is characterized by the presence of microcephaly and a tenfold increase in the levels of urinary organic acid 2-ketoglutarate. To date, all affected individuals within the Old Order Amish population (in which the prevalence of this condition in this population is approximately 1 in 500 births) are homozygous for a founder mutation in SLC25A19. McDonnell et al. identified mutations in STAMBP in a cohort of patients with Microcephaly-Capillary malformation (MIC-CAP) syndrome [OMIM#606247]. MIC-CAP is characterized by small scattered capillary malformations, congenital microcephaly, early-onset intractable epilepsy, profound global developmental delay, spastic quardriparesis, hypoplastic distal phalanges and poor growth. Mutations in ZEB2 are associated with Mowat-Wilson syndrome (MWS) [OMIM # 235730], which is characterized by distinctive facial features, moderate-to-severe mental retardation, microcephaly and seizures. Microcephaly may be either congenital or acquired postnatally. Congenital anomalies are also common, including Hirschsprung disease, genitourinary anomalies, congenital heart defects, agenesis of the corpus callosum and eye anomalies. Mutations in the ASPM gene are the most common cause of autosomal recessive primary microcephaly. Approximately 40% of patients with a strict diagnosis of MCPH have mutations in ASPM. However, fewer patients (<10%) with a less restrictive phenotype have mutations in ASPM. Genin et al. (2012) identified the same CASC5 frameshift mutation in the homozygous state in three separate consanguineous families with autosomal recessive primary microcephaly. Homozygous mutations in CDK5RAP2 have been identified in three Pakistani families with autosomal recessive primary microcephaly. Four Pakistani families with autosomal recessive primary microcephaly have been reported with homozygous mutations in CENPJ. Hussain et al. identified a homozygous frameshift mutation in a consanguineous family with two siblings affected by autosomal recessive primary microcephaly. Homozygous or compound heterozygous mutations in the CEP152 gene were identified in 3 unrelated Canadian families with MCPH. Homozygous mutations in MCPH1 have been reported in multiple populations, including at least one Pakistani family and at least one Caucasian family. Kumar et al (2009) reported three Indian families with autosomal recessive primary microcephaly that were homozygous for mutations in STIL. Mutations in WDR62 have been reported in a subset of patients with microcephaly, cortical malformations, and moderate to severe ID. In addition to microcephaly, these patients also have various brain malformations including callosal abnormalities, polymicrogyria, schizencephaly and subcortical nodular heterotopia. A subset have seizures. Homozygous missense and frameshift mutations were first reported in seven consanguineous families. Yang et al. (2012) identified a homozygous mutation in ZNF335 in a large consanguineous Arab-Israeli family with severe autosomal recessive primary microcephaly. CDKL5 mutations have been described in females X-linked infantile spasms [OMIM#300672], which is associated with early-onset refractory epilepsy, severe developmental delay, absent or limited speech, in addition to postnatal microcephaly and hand stereotypies in some patients. Mutations in males are associated with a more severe phenotype of early-onset tonic and myoclonic seizures, intractable infantile spasms, severe global developmental delay, cortical visual impairment and sleep disturbances. Abnormalities of the FOXG1 gene have been identified in patients with the congenital variant of Rett syndrome [OMIM#613454]. Patients with FOXG1 mutations typically have early onset epilepsy, severe cognitive impairment, progressive postnatal microcephaly, postnatal growth deficiency and dyskinetic movement disorders. Unlike classic Rett syndrome there is typically no observed period of normal development prior to onset of symptoms. MECP2 mutations are present in 70-90% of females with classic Rett syndrome [OMIM#312750] and approximately 20% of females with atypical Rett syndrome. Classic Rett syndrome is a progressive disorder characterized by acquired microcephaly, epilepsy, poor growth, loss of purposeful hand movements, and autistic behaviors, following a period of normal growth and development. MECP2 mutations appear to be more common in females than in males, and the majority of cases are de novo. There have been reports of unaffected or mildly affected MECP2 carrier females due to skewed X inactivation. A homozygous missense mutation in MED17 was identified in 5 infants from 4 Jewish families with postnatal progressive microcephaly with seizures and brain atrophy [OMIM#613668]. Mutations in RAB18, RAB3GAP1 and RAB3GAP2 are associated with Warburg Micro syndrome [OMIM#600118], which is characterized by ocular and neurodevelopmental abnormalities and hypothalamic hypogonadism. Key clinical features include microcephaly, microphthalmia, microcornia, congenital cataracts, optic atrophy, cortical dysplasia and atrophy, congenital hypotonia, severe intellectual disability, and spastic diplegia. Brain magnetic resonance imaging (MRI) of affected individuals consistently shows polymicrogyria in the frontal and parietal lobes, wide sylvian fissures, thin corpus callosum and increased subdural spaces. Glucose transporter-1 (GLUT-1) deficiency syndrome [OMIM#612126] is caused by mutations in the SLC2A1 gene, which lead to impaired glucose transport in the brain. The classic GLUT-1 deficiency syndrome presentation is drug-resistant infantile-onset seizures, acquired microcephaly, developmental delay, hypotonia, spasticity, ataxia and dystonia. A ketogenic diet is effective in mitigating clinical findings in affected individuals. Mutations in the SLC9A6 gene have been identified in patients with X-linked Angelman-like syndrome [OMIM#300243]. Features of males with SLC9A6 mutations include progressive microcephaly, grand mal epilepsy, lack of speech, trunal ataxia, excessive drooling, and a happy demeanor with spontaneous smiling and laughter. Mutations in SLC9A6 result in clinical features in affected males and occasionally some mild features in carrier females. Mutations in TCF4 are associated with Pitt-Hopkins syndrome (PHS) [OMIM#610954]. PHS is characterized by severe mental retardation and dysmorphic facial features, which tend to coarsen with age. Other common features include acquired microcephaly, epilepsy, hyperventilation episodes, short stature, stereotypic hand movements, and absent speech. Mutations in UBE3A are one of the causes of Angelman syndrome [OMIM#105830], which is characterized by severe intellectual disability, frequent laughing/smiling, easy excitability, and severe speech impairment. Other characteristics noted in over 80% of patients include microcephaly, seizures, and a specific, abnormal EEG pattern. Most mutations in UBE3A are de novo, with a <1% recurrence rate, however some cases may be familial. View more

View citations (40)

Jackson AP, Eastwood H, Bell SM, Adu J, Toomes C, Carr IM, Roberts E, Hampshire DJ, Crow YJ, Mighell AJ, Karbani G, Jafri H, Rashid Y, Mueller RF, Markham AF, Woods CG. Identification of microcephalin, a protein implicated in determining the size of the human brain. Am J Hum Genet. 2002;71(1):136-42. doi:10.1086/341283. Epub 2002 Jun 03. PMID: 12046007.
Bond J, Roberts E, Mochida GH, Hampshire DJ, Scott S, Askham JM, Springell K, Mahadevan M, Crow YJ, Markham AF, Walsh CA, Woods CG. ASPM is a major determinant of cerebral cortical size. Nat Genet. 2002;32(2):316-20. doi:10.1038/ng995. Epub 2002 Sep 23. PMID: 12355089.
O'Driscoll M, Ruiz-Perez VL, Woods CG, Jeggo PA, Goodship JA. A splicing mutation affecting expression of ataxia-telangiectasia and Rad3-related protein (ATR) results in Seckel syndrome. Nat Genet. 2003;33(4):497-501. doi:10.1038/ng1129. Epub 2003 Mar 17. PMID: 12640452.
Sheen VL, Ganesh VS, Topcu M, Sebire G, Bodell A, Hill RS, Grant PE, Shugart YY, Imitola J, Khoury SJ, Guerrini R, Walsh CA. Mutations in ARFGEF2 implicate vesicle trafficking in neural progenitor proliferation and migration in the human cerebral cortex. Nat Genet. 2004;36(1):69-76. doi:10.1038/ng1276. Epub 2003 Nov 30. PMID: 14647276.
Trimborn M, Bell SM, Felix C, Rashid Y, Jafri H, Griffiths PD, Neumann LM, Krebs A, Reis A, Sperling K, Neitzel H, Jackson AP. Mutations in microcephalin cause aberrant regulation of chromosome condensation. Am J Hum Genet. 2004;75(2):261-6. doi:10.1086/422855. Epub 2004 Jun 15. PMID: 15199523.
Mutations of the catalytic subunit of RAB3GAP cause Warburg Micro syndrome. Aligianis IA, et al. Nat Genet. 2005;37(3):221-3. doi:10.1038/ng1517. PMID: 15696165.
Bond J, Roberts E, Springell K, Lizarraga SB, Scott S, Higgins J, Hampshire DJ, Morrison EE, Leal GF, Silva EO, Costa SM, Baralle D, Raponi M, Karbani G, Rashid Y, Jafri H, Bennett C, Corry P, Walsh CA, Woods CG. A centrosomal mechanism involving CDK5RAP2 and CENPJ controls brain size. Nat Genet. 2005;37(4):353-5. doi:10.1038/ng1539. Epub 2005 Mar 27. PMID: 15793586.
Woods CG, Bond J, Enard W. Autosomal recessive primary microcephaly (MCPH): a review of clinical, molecular, and evolutionary findings. Am J Hum Genet. 2005;76(5):717-28. doi:10.1086/429930. Epub 2005 Mar 31. PMID: 15806441.
The first missense alteration in the MCPH1 gene causes autosomal recessive microcephaly with an extremely mild cellular and clinical phenotype. Trimborn M, et al. Hum Mutat. 2005;26(5):496. doi:10.1002/humu.9382. PMID: 16211557.
Gul A, Hassan MJ, Hussain S, Raza SI, Chishti MS, Ahmad W. A novel deletion mutation in CENPJ gene in a Pakistani family with autosomal recessive primary microcephaly. J Hum Genet. 2006;51(9):760-764. doi:10.1007/s10038-006-0017-1. Epub 2006 Aug 10. PMID: 16900296.
Hassan MJ, Khurshid M, Azeem Z, John P, Ali G, Chishti MS, Ahmad W. Previously described sequence variant in CDK5RAP2 gene in a Pakistani family with autosomal recessive primary microcephaly. BMC Med Genet. 2007;8:58. doi:10.1186/1471-2350-8-58. Epub 2007 Sep 01. PMID: 17764569.
Rauch A, Thiel CT, Schindler D, Wick U, Crow YJ, Ekici AB, van Essen AJ, Goecke TO, Al-Gazali L, Chrzanowska KH, Zweier C, Brunner HG, Becker K, Curry CJ, Dallapiccola B, Devriendt K, Dörfler A, Kinning E, Megarbane A, Meinecke P, Semple RK, Spranger S, Toutain A, Trembath RC, Voss E, Wilson L, Hennekam R, de Zegher F, Dörr HG, Reis A. Mutations in the pericentrin (PCNT) gene cause primordial dwarfism. Science. 2008;319(5864):816-9. doi:10.1126/science.1151174. Epub 2008 Jan 03. PMID: 18174396.
Gilfillan GD, Selmer KK, Roxrud I, Smith R, Kyllerman M, Eiklid K, Kroken M, Mattingsdal M, Egeland T, Stenmark H, Sjøholm H, Server A, Samuelsson L, Christianson A, Tarpey P, Whibley A, Stratton MR, Futreal PA, Teague J, Edkins S, Gecz J, Turner G, Raymond FL, Schwartz C, Stevenson RE, Undlien DE, Strømme P. SLC9A6 mutations cause X-linked mental retardation, microcephaly, epilepsy, and ataxia, a phenotype mimicking Angelman syndrome. Am J Hum Genet. 2008;82(4):1003-10. doi:10.1016/j.ajhg.2008.01.013. Epub 2008 Mar 13. PMID: 18342287.
Nicholas AK, Swanson EA, Cox JJ, Karbani G, Malik S, Springell K, Hampshire D, Ahmed M, Bond J, Di Benedetto D, Fichera M, Romano C, Dobyns WB, Woods CG. The molecular landscape of ASPM mutations in primary microcephaly. J Med Genet. 2009;46(4):249-53. doi:10.1136/jmg.2008.062380. Epub 2008 Nov 21. PMID: 19028728.
Mutations of CASK cause an X-linked brain malformation phenotype with microcephaly and hypoplasia of the brainstem and cerebellum. Najm J, et al. Nat Genet. 2008;40(9):1065-7. doi:10.1038/ng.194. PMID: 19165920.
Mutational, functional, and expression studies of the TCF4 gene in Pitt-Hopkins syndrome. de Pontual L, et al. Hum Mutat. 2009;30(4):669-76. doi:10.1002/humu.20935. PMID: 19235238.
Brockmann K. The expanding phenotype of GLUT1-deficiency syndrome. Brain Dev. 2009;31(7):545-52. doi:10.1016/j.braindev.2009.02.008. Epub 2009 Mar 21. PMID: 19304421.
Shen J, Gilmore EC, Marshall CA, Haddadin M, Reynolds JJ, Eyaid W, Bodell A, Barry B, Gleason D, Allen K, Ganesh VS, Chang BS, Grix A, Hill RS, Topcu M, Caldecott KW, Barkovich AJ, Walsh CA. Mutations in PNKP cause microcephaly, seizures and defects in DNA repair. Nat Genet. 2010;42(3):245-9. doi:10.1038/ng.526. Epub 2010 Jan 31. PMID: 20118933.
Tabarki B, Thabet F, Alfadhel M. -Related Thiamine Metabolism Dysfunction. 2003 Sep 04 [updated 2023 Mar 30]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. PMID: 20301539.
Stevenson RE. Alpha-Thalassemia X-Linked Intellectual Disability Syndrome. 2000 Jun 19 [updated 2020 May 28]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. PMID: 20301622.
Morris-Rosendahl DJ, Segel R, Born AP, Conrad C, Loeys B, Brooks SS, Müller L, Zeschnigk C, Botti C, Rabinowitz R, Uyanik G, Crocq MA, Kraus U, Degen I, Faes F. New RAB3GAP1 mutations in patients with Warburg Micro Syndrome from different ethnic backgrounds and a possible founder effect in the Danish. Eur J Hum Genet. 2010;18(10):1100-6. doi:10.1038/ejhg.2010.79. Epub 2010 May 26. PMID: 20512159.
Yu TW, Mochida GH, Tischfield DJ, Sgaier SK, Flores-Sarnat L, Sergi CM, Topçu M, McDonald MT, Barry BJ, Felie JM, Sunu C, Dobyns WB, Folkerth RD, Barkovich AJ, Walsh CA. Mutations in WDR62, encoding a centrosome-associated protein, cause microcephaly with simplified gyri and abnormal cortical architecture. Nat Genet. 2010;42(11):1015-20. doi:10.1038/ng.683. Epub 2010 Oct 03. PMID: 20890278.
Kaufmann R, Straussberg R, Mandel H, Fattal-Valevski A, Ben-Zeev B, Naamati A, Shaag A, Zenvirt S, Konen O, Mimouni-Bloch A, Dobyns WB, Edvardson S, Pines O, Elpeleg O. Infantile cerebral and cerebellar atrophy is associated with a mutation in the MED17 subunit of the transcription preinitiation mediator complex. Am J Hum Genet. 2010;87(5):667-70. doi:10.1016/j.ajhg.2010.09.016. Epub 2010 Oct 14. PMID: 20950787.
Loss-of-function mutations in RAB18 cause Warburg micro syndrome. Bem D, et al. Am J Hum Genet. 2011;88(4):499-507. doi:10.1016/j.ajhg.2011.03.012. PMID: 21473985.
Bakircioglu M, Carvalho OP, Khurshid M, Cox JJ, Tuysuz B, Barak T, Yilmaz S, Caglayan O, Dincer A, Nicholas AK, Quarrell O, Springell K, Karbani G, Malik S, Gannon C, Sheridan E, Crosier M, Lisgo SN, Lindsay S, Bilguvar K, Gergely F, Gunel M, Woods CG. The essential role of centrosomal NDE1 in human cerebral cortex neurogenesis. Am J Hum Genet. 2011;88(5):523-35. doi:10.1016/j.ajhg.2011.03.019. Epub 2011 Apr 28. PMID: 21529752.
Sir JH, Barr AR, Nicholas AK, Carvalho OP, Khurshid M, Sossick A, Reichelt S, D'Santos C, Woods CG, Gergely F. A primary microcephaly protein complex forms a ring around parental centrioles. Nat Genet. 2011;43(11):1147-53. doi:10.1038/ng.971. Epub 2011 Oct 09. PMID: 21983783.
Qvist P, Huertas P, Jimeno S, Nyegaard M, Hassan MJ, Jackson SP, Børglum AD. CtIP Mutations Cause Seckel and Jawad Syndromes. PLoS Genet. 2011;7(10):e1002310. doi:10.1371/journal.pgen.1002310. Epub 2011 Oct 06. PMID: 21998596.
Hussain MS, Baig SM, Neumann S, Nürnberg G, Farooq M, Ahmad I, Alef T, Hennies HC, Technau M, Altmüller J, Frommolt P, Thiele H, Noegel AA, Nürnberg P. A truncating mutation of CEP135 causes primary microcephaly and disturbed centrosomal function. Am J Hum Genet. 2012;90(5):871-8. doi:10.1016/j.ajhg.2012.03.016. Epub 2012 Apr 19. PMID: 22521416.
Genin A, Desir J, Lambert N, Biervliet M, Van Der Aa N, Pierquin G, Killian A, Tosi M, Urbina M, Lefort A, Libert F, Pirson I, Abramowicz M. Kinetochore KMN network gene CASC5 mutated in primary microcephaly. Hum Mol Genet. 2012;21(24):5306-17. doi:10.1093/hmg/dds386. Epub 2012 Sep 13. PMID: 22983954.
Guerrini R, Parrini E. Epilepsy in Rett syndrome, and CDKL5- and FOXG1-gene-related encephalopathies. Epilepsia. 2012;53(12):2067-78. doi:10.1111/j.1528-1167.2012.03656.x. Epub 2012 Sep 21. PMID: 22998673.
Microcephaly gene links trithorax and REST/NRSF to control neural stem cell proliferation and differentiation. Yang YJ, et al. Cell. 2012;151(5):1097-112. doi:10.1016/j.cell.2012.10.043. PMID: 23178126.
McDonell LM, Mirzaa GM, Alcantara D, Schwartzentruber J, Carter MT, Lee LJ, Clericuzio CL, Graham JM, Morris-Rosendahl DJ, Polster T, Acsadi G, Townshend S, Williams S, Halbert A, Isidor B, David A, Smyser CD, Paciorkowski AR, Willing M, Woulfe J, Das S, Beaulieu CL, Marcadier J, , Geraghty MT, Frey BJ, Majewski J, Bulman DE, Dobyns WB, O'Driscoll M, Boycott KM. Mutations in STAMBP, encoding a deubiquitinating enzyme, cause microcephaly-capillary malformation syndrome. Nat Genet. 2013;45(5):556-62. doi:10.1038/ng.2602. Epub 2013 Mar 31. PMID: 23542699.
CDKL5 and ARX mutations in males with early-onset epilepsy. Mirzaa GM, et al. Pediatr Neurol. 2013;48(5):367-77. doi:10.1016/j.pediatrneurol.2012.12.030. PMID: 23583054.
Adam M, Bean L, Miller V. Mowat-Wilson Syndrome. In: Pagon R, Bird T, Dolan C, eds. GeneReviews [Internet]. Seattle: University of Washington, 2007.
Christodoulou J, Ho G. MECP2-Related Disorders. In: Pagon R, Bird T, Dolan C, eds. GeneReviews [Internet]. Seattle: University of Washington, 2001.
Dagli A, Williams C. Angelman Syndrome. In: Pagon R, Bird T, Dolan C, eds. GeneReviews [Internet]. Seattle: University of Washington, 1998.
Faivre L, Cormier-Daire V. Seckel Syndrome. Orphanet encyclopedia, 2005.
S P. Autosomal Recessive Microcephaly. GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2013., 2009 Sep 1.
https://www.ncbi.nlm.nih.gov/books/NBK1365
https://www.ncbi.nlm.nih.gov/books/NBK1449

Clinical utility:

Establish or confirm diagnosis

View citations (40)

Jackson AP, Eastwood H, Bell SM, Adu J, Toomes C, Carr IM, Roberts E, Hampshire DJ, Crow YJ, Mighell AJ, Karbani G, Jafri H, Rashid Y, Mueller RF, Markham AF, Woods CG. Identification of microcephalin, a protein implicated in determining the size of the human brain. Am J Hum Genet. 2002;71(1):136-42. doi:10.1086/341283. Epub 2002 Jun 03. PMID: 12046007.
Bond J, Roberts E, Mochida GH, Hampshire DJ, Scott S, Askham JM, Springell K, Mahadevan M, Crow YJ, Markham AF, Walsh CA, Woods CG. ASPM is a major determinant of cerebral cortical size. Nat Genet. 2002;32(2):316-20. doi:10.1038/ng995. Epub 2002 Sep 23. PMID: 12355089.
O'Driscoll M, Ruiz-Perez VL, Woods CG, Jeggo PA, Goodship JA. A splicing mutation affecting expression of ataxia-telangiectasia and Rad3-related protein (ATR) results in Seckel syndrome. Nat Genet. 2003;33(4):497-501. doi:10.1038/ng1129. Epub 2003 Mar 17. PMID: 12640452.
Sheen VL, Ganesh VS, Topcu M, Sebire G, Bodell A, Hill RS, Grant PE, Shugart YY, Imitola J, Khoury SJ, Guerrini R, Walsh CA. Mutations in ARFGEF2 implicate vesicle trafficking in neural progenitor proliferation and migration in the human cerebral cortex. Nat Genet. 2004;36(1):69-76. doi:10.1038/ng1276. Epub 2003 Nov 30. PMID: 14647276.
Trimborn M, Bell SM, Felix C, Rashid Y, Jafri H, Griffiths PD, Neumann LM, Krebs A, Reis A, Sperling K, Neitzel H, Jackson AP. Mutations in microcephalin cause aberrant regulation of chromosome condensation. Am J Hum Genet. 2004;75(2):261-6. doi:10.1086/422855. Epub 2004 Jun 15. PMID: 15199523.
Mutations of the catalytic subunit of RAB3GAP cause Warburg Micro syndrome. Aligianis IA, et al. Nat Genet. 2005;37(3):221-3. doi:10.1038/ng1517. PMID: 15696165.
Bond J, Roberts E, Springell K, Lizarraga SB, Scott S, Higgins J, Hampshire DJ, Morrison EE, Leal GF, Silva EO, Costa SM, Baralle D, Raponi M, Karbani G, Rashid Y, Jafri H, Bennett C, Corry P, Walsh CA, Woods CG. A centrosomal mechanism involving CDK5RAP2 and CENPJ controls brain size. Nat Genet. 2005;37(4):353-5. doi:10.1038/ng1539. Epub 2005 Mar 27. PMID: 15793586.
Woods CG, Bond J, Enard W. Autosomal recessive primary microcephaly (MCPH): a review of clinical, molecular, and evolutionary findings. Am J Hum Genet. 2005;76(5):717-28. doi:10.1086/429930. Epub 2005 Mar 31. PMID: 15806441.
The first missense alteration in the MCPH1 gene causes autosomal recessive microcephaly with an extremely mild cellular and clinical phenotype. Trimborn M, et al. Hum Mutat. 2005;26(5):496. doi:10.1002/humu.9382. PMID: 16211557.
Gul A, Hassan MJ, Hussain S, Raza SI, Chishti MS, Ahmad W. A novel deletion mutation in CENPJ gene in a Pakistani family with autosomal recessive primary microcephaly. J Hum Genet. 2006;51(9):760-764. doi:10.1007/s10038-006-0017-1. Epub 2006 Aug 10. PMID: 16900296.
Hassan MJ, Khurshid M, Azeem Z, John P, Ali G, Chishti MS, Ahmad W. Previously described sequence variant in CDK5RAP2 gene in a Pakistani family with autosomal recessive primary microcephaly. BMC Med Genet. 2007;8:58. doi:10.1186/1471-2350-8-58. Epub 2007 Sep 01. PMID: 17764569.
Rauch A, Thiel CT, Schindler D, Wick U, Crow YJ, Ekici AB, van Essen AJ, Goecke TO, Al-Gazali L, Chrzanowska KH, Zweier C, Brunner HG, Becker K, Curry CJ, Dallapiccola B, Devriendt K, Dörfler A, Kinning E, Megarbane A, Meinecke P, Semple RK, Spranger S, Toutain A, Trembath RC, Voss E, Wilson L, Hennekam R, de Zegher F, Dörr HG, Reis A. Mutations in the pericentrin (PCNT) gene cause primordial dwarfism. Science. 2008;319(5864):816-9. doi:10.1126/science.1151174. Epub 2008 Jan 03. PMID: 18174396.
Gilfillan GD, Selmer KK, Roxrud I, Smith R, Kyllerman M, Eiklid K, Kroken M, Mattingsdal M, Egeland T, Stenmark H, Sjøholm H, Server A, Samuelsson L, Christianson A, Tarpey P, Whibley A, Stratton MR, Futreal PA, Teague J, Edkins S, Gecz J, Turner G, Raymond FL, Schwartz C, Stevenson RE, Undlien DE, Strømme P. SLC9A6 mutations cause X-linked mental retardation, microcephaly, epilepsy, and ataxia, a phenotype mimicking Angelman syndrome. Am J Hum Genet. 2008;82(4):1003-10. doi:10.1016/j.ajhg.2008.01.013. Epub 2008 Mar 13. PMID: 18342287.
Nicholas AK, Swanson EA, Cox JJ, Karbani G, Malik S, Springell K, Hampshire D, Ahmed M, Bond J, Di Benedetto D, Fichera M, Romano C, Dobyns WB, Woods CG. The molecular landscape of ASPM mutations in primary microcephaly. J Med Genet. 2009;46(4):249-53. doi:10.1136/jmg.2008.062380. Epub 2008 Nov 21. PMID: 19028728.
Mutations of CASK cause an X-linked brain malformation phenotype with microcephaly and hypoplasia of the brainstem and cerebellum. Najm J, et al. Nat Genet. 2008;40(9):1065-7. doi:10.1038/ng.194. PMID: 19165920.
Mutational, functional, and expression studies of the TCF4 gene in Pitt-Hopkins syndrome. de Pontual L, et al. Hum Mutat. 2009;30(4):669-76. doi:10.1002/humu.20935. PMID: 19235238.
Brockmann K. The expanding phenotype of GLUT1-deficiency syndrome. Brain Dev. 2009;31(7):545-52. doi:10.1016/j.braindev.2009.02.008. Epub 2009 Mar 21. PMID: 19304421.
Shen J, Gilmore EC, Marshall CA, Haddadin M, Reynolds JJ, Eyaid W, Bodell A, Barry B, Gleason D, Allen K, Ganesh VS, Chang BS, Grix A, Hill RS, Topcu M, Caldecott KW, Barkovich AJ, Walsh CA. Mutations in PNKP cause microcephaly, seizures and defects in DNA repair. Nat Genet. 2010;42(3):245-9. doi:10.1038/ng.526. Epub 2010 Jan 31. PMID: 20118933.
Tabarki B, Thabet F, Alfadhel M. -Related Thiamine Metabolism Dysfunction. 2003 Sep 04 [updated 2023 Mar 30]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. PMID: 20301539.
Stevenson RE. Alpha-Thalassemia X-Linked Intellectual Disability Syndrome. 2000 Jun 19 [updated 2020 May 28]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. PMID: 20301622.
Morris-Rosendahl DJ, Segel R, Born AP, Conrad C, Loeys B, Brooks SS, Müller L, Zeschnigk C, Botti C, Rabinowitz R, Uyanik G, Crocq MA, Kraus U, Degen I, Faes F. New RAB3GAP1 mutations in patients with Warburg Micro Syndrome from different ethnic backgrounds and a possible founder effect in the Danish. Eur J Hum Genet. 2010;18(10):1100-6. doi:10.1038/ejhg.2010.79. Epub 2010 May 26. PMID: 20512159.
Yu TW, Mochida GH, Tischfield DJ, Sgaier SK, Flores-Sarnat L, Sergi CM, Topçu M, McDonald MT, Barry BJ, Felie JM, Sunu C, Dobyns WB, Folkerth RD, Barkovich AJ, Walsh CA. Mutations in WDR62, encoding a centrosome-associated protein, cause microcephaly with simplified gyri and abnormal cortical architecture. Nat Genet. 2010;42(11):1015-20. doi:10.1038/ng.683. Epub 2010 Oct 03. PMID: 20890278.
Kaufmann R, Straussberg R, Mandel H, Fattal-Valevski A, Ben-Zeev B, Naamati A, Shaag A, Zenvirt S, Konen O, Mimouni-Bloch A, Dobyns WB, Edvardson S, Pines O, Elpeleg O. Infantile cerebral and cerebellar atrophy is associated with a mutation in the MED17 subunit of the transcription preinitiation mediator complex. Am J Hum Genet. 2010;87(5):667-70. doi:10.1016/j.ajhg.2010.09.016. Epub 2010 Oct 14. PMID: 20950787.
Loss-of-function mutations in RAB18 cause Warburg micro syndrome. Bem D, et al. Am J Hum Genet. 2011;88(4):499-507. doi:10.1016/j.ajhg.2011.03.012. PMID: 21473985.
Bakircioglu M, Carvalho OP, Khurshid M, Cox JJ, Tuysuz B, Barak T, Yilmaz S, Caglayan O, Dincer A, Nicholas AK, Quarrell O, Springell K, Karbani G, Malik S, Gannon C, Sheridan E, Crosier M, Lisgo SN, Lindsay S, Bilguvar K, Gergely F, Gunel M, Woods CG. The essential role of centrosomal NDE1 in human cerebral cortex neurogenesis. Am J Hum Genet. 2011;88(5):523-35. doi:10.1016/j.ajhg.2011.03.019. Epub 2011 Apr 28. PMID: 21529752.
Sir JH, Barr AR, Nicholas AK, Carvalho OP, Khurshid M, Sossick A, Reichelt S, D'Santos C, Woods CG, Gergely F. A primary microcephaly protein complex forms a ring around parental centrioles. Nat Genet. 2011;43(11):1147-53. doi:10.1038/ng.971. Epub 2011 Oct 09. PMID: 21983783.
Qvist P, Huertas P, Jimeno S, Nyegaard M, Hassan MJ, Jackson SP, Børglum AD. CtIP Mutations Cause Seckel and Jawad Syndromes. PLoS Genet. 2011;7(10):e1002310. doi:10.1371/journal.pgen.1002310. Epub 2011 Oct 06. PMID: 21998596.
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https://www.ncbi.nlm.nih.gov/books/NBK1365
https://www.ncbi.nlm.nih.gov/books/NBK1449

Target population:

The target population for this test is patients suspected of having a diagnosis of Microcephaly.

Variant Interpretation:

What is the protocol for interpreting a variation as a VUS?
Variants are identified and evaluated using a custom collection of bioinformatic tools and comprehensively interpreted by our team of directors and genetic counselors.

Will the lab re-contact the ordering physician if variant interpretation changes?
Yes.

Research:

Is research allowed on the sample after clinical testing is complete?
http://dnatesting.uchicago.edu/research-consent-form

Recommended fields not provided:

Are family members with defined clinical status recruited to assess significance of VUS without charge?, Sample negative report, Sample positive report

Technical Information

Availability:

Tests performed
Entire test performed in-house

Analytical Validity:

Analytical Sensitivity 99-100% Accuracy 100% Precision 100%

Assay limitations:

This assay covers the coding and immediate flanking regions of the included genes. Variants in the promoter region and in other non-coding regions will not be detected. Variants that occur within regions of high homology and/or repetitiveness may not be detected due to issues with alignment. The technical sensitivity of … View more

Proficiency testing (PT):

Is proficiency testing performed for this test?
Yes

Method used for proficiency testing:
Formal PT program

PT Provider:
American College of Medical Genetics / College of American Pathologists, ACMG/CAP

VUS:

Software used to interpret novel variations
A custom collection of bioinformatics tools

Laboratory's policy on reporting novel variations
The laboratory reports novel variations.

Recommended fields not provided:

Test Confirmation, Citations to support assay limitations, Description of internal test validation method, Citations for Analytical validity, Description of PT method, Major CAP category, CAP category, CAP test list

Regulatory Approval

FDA Review:

Category: FDA exercises enforcement discretion

Additional Information

Reviews:

PubMed Clinical Queries

Clinical resources:

Molecular resources:

View ARFGEF2 variations in ClinVar

RefSeqGene

Coriell Institute for Medical Research

Consumer resources:

Genetic Alliance

MalaCards

NCATS Office of Rare Diseases Research (GARD)

MedlinePlus

IMPORTANT NOTE: NIH does not independently verify information submitted to GTR; it relies on submitters to provide information that is accurate and not misleading. NIH makes no endorsements of tests or laboratories listed in GTR. GTR is not a substitute for medical advice. Patients and consumers with specific questions about a genetic test should contact a health care provider or a genetics professional.