Brain malformations

The Hehr laboratory has been working for more than 20 years on genetic factors affecting human brain development with a main focus on pathogenesis and genotype phenotype correlations in holoprosencephaly and disorders of cortical development including classic and cobblestone lissencephalies, periventricular nodular heterotopia, double cortex and polymicrogyria.

We offer in our accredited laboratory:

  • pretest evaluation of your patients clinical information and cerebral MR imaging in order to develop an individual genetic testing strategy;
  • diagnostic prenatal and postnatal genetic testing by Sanger sequencing as well as MLPA analysis
  • Next Generation Sequencing with disease specific panels for HoloprosencephalyHPE and for Neuronal Migration DisordersNM
  • carrier testing
  • rapid prenatal genetic testing for pregnancies with sonografically suspected fetal brain malformation
  • prenatal carrier testing in subsequent pregnancies  for disorders with clinical manifestation prior to adolescence.

All identified sequence alterations, relevant or potentially relevant for the clinical findings of your patient, are

  • confirmed by Sanger sequencing,
  • carefully assessed using our in house evaluation workflow including comparison with the human reference genome hg19, publically available and our own extensive mutation database as well as in silico prediction of functional consequences applying different algorithms,
  • rated and summarized in an individual medical report considering provided clinical and imaging data.

In addition to our NGS panels for

  • HoloprosencephalyHPE, covering 15 HPE-associated genes and 16 genes with overlapping phenotypes and
  • Neuronal Migration DisordersNM, covering 107 associated genes

we offer at our center genetic testing by Sanger sequencing, MLPA(+MLPA) and Linkage analysis (+Linkage) for:

Disease Disease
OMIM
Gene Gene
OMIM
Chromosomal
location

Brain malformations and congenital muscular dystrophies

NGS Panel Brain malformations  
HPE Panel (15 HPE-associated genes and 16 genes with overlapping phenotype)HPE pdf
Panel Neuronal migration disorders (107 genes associated with Lissencephaly, Double cortex, Microcephaly, PMG)NM pdf

Double Cortex

Double cortex/subcortical laminar heterotopia(+MLPA) 300067
607432
611603
DCX NM
LIS1 (PAFAH1B1) NM
TUBA1A NM
300121
601545
602529
Xq23
17p13.3
12q13.12
Holoprosencephaly (HPE) 236100      
HPE Panel (15 HPE-associated genes and 16 genes with overlapping phenotype)HPE pdf
HPE2 (+MLPA) 157170 SIX3 HPE, NM 603714 2p21
HPE3 (+MLPA) 142945 SHH HPE, NM 600725 7q36.3
HPE4 (+MLPA) 142946 TGIF HPE, NM 602630 18p11.31
HPE5 (+MLPA) 609637 ZIC2 HPE, NM 603073 13q32.3
HPE7 (+MLPA) 610828 PTCH1 HPE 601309 9q22.32
HPE9 (+MLPA) 610829 GLI2 HPE 165230 2q14.2
Holoprosencephaly/visceral Heterotaxy 270100 NODAL HPE 601265 10q22.1
Lissencephaly 607432      
Panel Neuronal migration disorders (107 genes associated with Lissencephaly, Double cortex, Microcephaly, PMG)NM pdf
Lissencephaly, X-linked (+MLPA) 300067 DCX NM 300121 Xq23
Lissencephaly, X-linked (XLAG) (+MLPA) 300215 ARXHPE, NM 300382 Xp21.3
Lissencephaly, classic, autosomal dominant (LIS1) (+MLPA) 607432 LIS1 (PAFAH1B1) NM 601545 17p13.3
Lissencephaly, autosomal dominant 611603 TUBA1A NM 602529 12q13.12
Microcephaly, primary autosomal recessive 251200      
Panel Neuronal migration disorders (107 genes associated with Lissencephaly, Double cortex, Microcephaly, PMG)NM pdf
Microcephaly, MCPH1 (+MLPA, Linkage) 251200 MCPH1 (Microcephalin) NM 607117 8p23.1
MCPH2 (+Linkage) 604317 WDR62 NM 613583 19q13.12
MCPH3 (only Linkage, NM + MLPA) 604804 CDK5RAP2 NM 608201 9q33.2
MCPH9 (only Linkage + NM) 614852 CEP152 NM 613529 15q21.1
MCPH5 (+MLPA, Linkage) 608716 ASPM NM 605481 1q31.3
MCPH6 (only Linkage, NM + MLPA) 608393 CENPJ NM 609279 13q12.12
MCPH7 (only Linkage, NM + MLPA) 612703 STIL NM 181590 1p33
Polymicrogyria        
Panel Neuronal migration disorders (107 genes associated with Lissencephaly, Double cortex, Microcephaly, PMG)NM pdf
Polymicrogyria, symmetric or asymmetric 610031 TUBB2B NM 612850 6p25.2
Polymicrogyria, bilateral frontoparietal 606854 GPR56 NM 604110 16q21
Polymicrogyria with optic nerve hypoplasia 613180 TUBA8 NM 605742 22q11.21
Rolandic epilepsy, mental retardation and speech dyspraxia 300643 SRPX2 NM 300642 Xq22.1
Periventricular nodular heterotopia (PVNH)        
Panel Neuronal migration disorders (107 genes associated with Lissencephaly, Double cortex, Microcephaly, PMG)NM pdf
PVNH, X-linked (+MLPA) 300049 FLNA NM 300017 Xq28
PVNH, autosomal-recessive with microcephaly (+Linkage) 608097 ARFGEF2 NM 605371 20q13.13
Other brain malformations        
Andermann syndrome (+Linkage) 218000 KCC3 (SLC12A6) 604878 15q14
Cerebellar Hypoplasia with mental retardation and distinctive facial appearance, X-linked 300486 OPHN1 NM 300127 Xq12
Cerebral cavernous malformations (+MLPA) 116860
603284
603285
CCM1 (KRIT1)
CCM2
CCM3 (PDCD10)
604214
607929
609118
7q21.2
7p13
3q26.1
Cortical dysplasia, complex, with other brain malformations 614039 TUBB3 NM 602661 16q24.3
Encephalopathy, acute, infection-induced 3 608033 RANBP2 601181 2q12.3
Epileptic encephalopathy, early infantile, 1 308350 ARX HPE, NM 300382 Xp21.3
Epileptic encephalopathy, early infantile, 1 308350 ARX HPE, NM 300382 Xp21.3
Holoprosencephaly/visceral Heterotaxy 270100
306955
NODAL HPE
ZIC3
601265
300265
10q22.1
Xq26.3
Hydrocephalus, X-linked (+MLPA) 307000 L1CAM HPE 308840 Xq28
Lissencephaly, X-linked (XLAG) (+MLPA) 300215
225790
ARXHPE, NM
FLVCR2 HPE, NM
300382
610865
Xp21.3
14q24.3
Lissencephaly, X-linked (XLAG) (+MLPA) 300215 ARX HPE, NM 300382 Xp21.3
Microphthalmia, syndromal (+MLPA) 610125
206900
OTX2 HPE
SOX2 HPE
600037
184429
14q22.3
3q26.33
Partington syndrome (+MLPA) 309510 ARX HPE, NM 300382 Xp21.3
Proud syndrome (+MLPA) 300004 ARX HPE, NM 300382 Xp21.3
Rett syndrome, congenital variant (+MLPA) 613454 FOXG1 NM 164874 14q12
Schizencephaly (+MLPA) 269160 SIX3 HPE, NM
SHH HPE, NM
EMX2 HPE, NM
603714
600725
600035
2p21
7q36.3
10q26.11
Septooptic dysplasia (+MLPA) 182230 HESX1 HPE 601802 3p14.3

Clinical research projects genotype phenotype correlation in patients with brain malformations

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We are currently undertaking two clinical research projects to further assess the genotype phenotype correlation and gene-based effects of medical and supportive therapies on the long-term clinical course and overall quality of life in patients with previously identified mutations:

Patients with classic lissencephalies and causal mutations in the genes LIS1/PAFAH1B1, DCX, TUBA1A and ARX

PI: Saskia Herbst, MD, contact: saskia.herbst@klinik.uni-regensburg.de

This study is approved by the local ethics committee of the University Hospital Regensburg

Project on adult patients with DCX associated Double cortex

 PI: Burkhard Kasper, MD, contact: burkhard.kasper@klinik.uni-erlangen.de

This study is approved by the local ethics committee of the University Hospital Erlangen

A third project is currently under review by our local ethics board for patients with congenital or limb girdle muscular dystrophies with or without brain malformations, resulting from defective O-glycosylation of alpha-dystrogylcan.

PI: Tobias Geis, MD, contact: tobias.geis@barmherzige-regensburg.de

Related Publications of our group

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Czeschik JC, Hehr U, Hartmann B, Lüdecke HJ, Rosenbaum T, Schweiger B, Wieczorek D. 160 kb deletion in ISPD unmasking a recessive mutation in a patient with Walker-Warburg syndrome. Eur J Med Genet. 2013 Oct 10. doi:pii: S1769-7212(13)00226-7.

Geis T, Marquard K, Rödl T, Reihle C, Schirmer S, von Kalle T, Bornemann A, Hehr U, Blankenburg M. Homozygous dystroglycan mutation associated with a novel muscle-eye-brain disease-like phenotype with multicystic leucodystrophy. Neurogenetics. 2013 Sep 20.

Kasper BS, Kurzbuch K, Chang BS, Pauli E, Hamer HM, Winkler J, Hehr UPaternal inheritance of classic X-linked bilateral periventricular nodular heterotopia. Am J Med Genet A. 2013 Jun;161(6):1323-8. doi: 10.1002/ajmg.a.35917.

Two-hit mechanism in cerebral cavernous malformation? A case of monozygotic twins with a CCM1/KRIT1 germline mutation. Dammann P, Hehr U, Weidensee S, Zhu Y, Gerlach R, Sure U. Neurosurg Rev. 2013 Jul;36(3):483-6.

Cushion TD, Dobyns WB, Mullins JG, Stoodley N, Chung SK, Fry AE, Hehr U, Gunny R, Aylsworth AS, Prabhakar P, Uyanik G, Rankin J, Rees MI, Pilz DT. Overlapping cortical malformations and mutations in TUBB2B and TUBA1A. Brain. 2013 Feb;136(Pt 2):536-48.

Uyanik G, Hehr U Angeborene Hirnfehlbildungen und geistige Behinderung Medizinische Genetik 04/2012; 21(2):217-223

Solomon BD, Bear KA, Wyllie A, Keaton AA, Dubourg C, David V, Mercier S, Odent S, Hehr U, Paulussen A, Clegg NJ, Delgado MR, Bale SJ, Lacbawan F, Ardinger HH, Aylsworth AS, Bhengu NL, Braddock S, Brookhyser K, Burton B, Gaspar H, Grix A, Horovitz D, Kanetzke E, Kayserili H, Lev D, Nikkel SM, Norton M, Roberts R, Saal H, Schaefer GB, Schneider A, Smith EK, Sowry E, Spence MA, Shalev SA, Steiner CE, Thompson EM, Winder TL, Balog JZ, Hadley DW, Zhou N, Pineda-Alvarez DE, Roessler E, Muenke M. Genotypic and phenotypic analysis of 396 individuals with mutations in Sonic Hedgehog. J Med Genet. 2012 Jul;49(7):473-9.

Bernstein JA, Bernstein D, Hehr U, Hudgins L. Familial cardiac valvulopathy due to filamin A mutation. Am J Med Genet A. 2011 Sep;155A(9):2236-41.

Hehr U, Schuierer G. Genetic assessment of cortical malformations. Neuropediatrics. 2011 Feb;42(2):43-50.

Ekici AB, Hilfinger D, Jatzwauk M, Thiel CT, Wenzel D, Lorenz I, Boltshauser E, Goecke TW, Staatz G, Morris-Rosendahl DJ, Sticht H, Hehr U, Reis A, Rauch A. Disturbed Wnt Signalling due to a Mutation in CCDC88C Causes an Autosomal Recessive Non-Syndromic Hydrocephalus with Medial Diverticulum. Mol Syndromol. 2010 Sep;1(3):99-112.

Yis U, Uyanik G, Heck PB, Smitka M, Nobel H, Ebinger F, Dirik E, Feng L, Kurul SH, Brocke K, Unalp A, Özer E, Cakmakci H, Sewry C, Cirak S, Muntoni F, Hehr U, Morris-Rosendahl DJ. Fukutin mutations in non-Japanese patients with congenital muscular dystrophy: less severe mutations predominate in patients with a non-Walker-Warburg phenotype. Neuromuscul Disord. 2011 Jan;21(1):20-30.

Hehr U, Uyanik G, Aigner L, Couillard-Despres S, Winkler J. DCX-Related Disorders. In: Pagon RA, Adam MP, Bird TD, Dolan CR, Fong CT, Stephens K, editors. GeneReviews™ [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2013.
2007 Oct 19 [updated 2011 Mar 24].

Hehr U, Pineda-Alvarez DE, Uyanik G, Hu P, Zhou N, Hehr A, Schell-Apacik C, Altus C, Daumer-Haas C, Meiner A, Steuernagel P, Roessler E, Winkler J, Muenke M. Heterozygous mutations in SIX3 and SHH are associated with schizencephaly and further expand the clinical spectrum of holoprosencephaly. Hum Genet. 2010 Mar;127(5):555-61.

Lommel M, Cirak S, Willer T, Hermann R, Uyanik G, van Bokhoven H, Körner C, Voit T, Barić I, Hehr U, Strahl S. Correlation of enzyme activity and clinical phenotype in POMT1-associated dystroglycanopathies. Neurology. 2010 Jan 12;74(2):157-64.

Rudnik-Schöneborn S, Hehr U, von Kalle T, Bornemann A, Winkler J, Zerres K. Andermann syndrome can be a phenocopy of hereditary motor and sensory neuropathy--report of a discordant sibship with a compound heterozygous mutation of the KCC3 gene. Neuropediatrics. 2009 Jun;40(3):129-33.

Solomon BD, Lacbawan F, Mercier S, Clegg NJ, Delgado MR, Rosenbaum K, Dubourg C, David V, Olney AH, Wehner LE, Hehr U, Bale S, Paulussen A, Smeets HJ, Hardisty E, Tylki-Szymanska A, Pronicka E, Clemens M, McPherson E, Hennekam RC, Hahn J, Stashinko E, Levey E, Wieczorek D, Roeder E, Schell-Apacik CC, Booth CW, Thomas RL, Kenwrick S, Cummings DA, Bous SM, Keaton A, Balog JZ, Hadley D, Zhou N, Long R, Vélez JI, Pineda-Alvarez DE, Odent S, Roessler E, Muenke M. Mutations in ZIC2 in human holoprosencephaly: description of a novel ZIC2 specific phenotype and comprehensive analysis of 157 individuals. J Med Genet. 2010 Aug;47(8):513-24.

Uyanik GHehr U Congenital brain malformations and mental retardation Medizinische Genetik - Med Genet. 01/2009; 21(2):217-223.

Judas M, Sedmak G, Rados M, Sarnavka V, Fumić K, Willer T, Gross CHehr U, Strahl S, Cuk M, Barić I. POMT1-associated walker-warburg syndrome: a disorder of dendritic development of neocortical neurons. Neuropediatrics. 2009 Feb;40(1):6-14.

Roessler E, El-Jaick KB, Dubourg C, Vélez JI, Solomon BD, Pineda-Alvarez DE, Lacbawan F, Zhou N, Ouspenskaia M, Paulussen A, Smeets HJ, Hehr U, Bendavid C, Bale S, Odent S, David V, Muenke M. The mutational spectrum of holoprosencephaly-associated changes within the SHH gene in humans predicts loss-of-function through either key structural alterations of the ligand or its altered synthesis. Hum Mutat. 2009 Oct;30(10):E921-35.

Schell-Apacik CC, Ertl-Wagner B, Panzel A, Klausener K, Rausch G, Muenke M, von Voss H, Hehr UMaternally inherited heterozygous sequence change in the sonic hedgehog gene in a male patient with bilateral closed-lip schizencephaly and partial absence of the corpus callosum. Am J Med Genet A. 2009 Jul;149A(7):1592-4.

Schell-Apacik CC, Ertl-Wagner B, Panzel A, Klausener K, Rausch G, Muenke M, von Voss H, Hehr UMaternally inherited heterozygous sequence change in the sonic hedgehog gene in a male patient with bilateral closed-lip schizencephaly and partial absence of the corpus callosum. Am J Med Genet A. 2009 Jul;149A(7):1592-4.

Lacbawan F, Solomon BD, Roessler E, El-Jaick K, Domené S, Vélez JI, Zhou N, Hadley D, Balog JZ, Long R, Fryer A, Smith W, Omar S, McLean SD, Clarkson K, Lichty A, Clegg NJ, Delgado MR, Levey E, Stashinko E, Potocki L, Vanallen MI, Clayton-Smith J, Donnai D, Bianchi DW, Juliusson PB, Njølstad PR, Brunner HG, Carey JC, Hehr U, Müsebeck J, Wieacker PF, Postra A, Hennekam RC, van den Boogaard MJ, van Haeringen A, Paulussen A, Herbergs J, Schrander-Stumpel CT, Janecke AR, Chitayat D, Hahn J, McDonald-McGinn DM, Zackai EH, Dobyns WB, Muenke M. Clinical spectrum of SIX3-associated mutations in holoprosencephaly: correlation between genotype, phenotype and function. J Med Genet. 2009 Jun;46(6):389-98.

Roessler E, Lacbawan F, Dubourg C, Paulussen A, Herbergs J, Hehr U, Bendavid C, Zhou N, Ouspenskaia M, Bale S, Odent S, David V, Muenke M. The full spectrum of holoprosencephaly-associated mutations within the ZIC2 gene in humans predicts loss-of-function as the predominant disease mechanism. Hum Mutat. 2009 Apr;30(4):E541-54.

Hehr U, Uyanik G, Gross C, Walter MC, Bohring A, Cohen M, Oehl-Jaschkowitz B, Bird LM, Shamdeen GM, Bogdahn U, Schuierer G, Topaloglu H, Aigner L, Lochmüller H, Winkler J. Novel POMGnT1 mutations define broader phenotypic spectrum of muscle-eye-brain disease. Neurogenetics. 2007 Nov;8(4):279-88.

Uyanik G, Morris-Rosendahl DJ, Stiegler J, Klapecki J, Gross C, Berman Y, Martin P, Dey L, Spranger S, Korenke GC, Schreyer I, Hertzberg C, Neumann TE, Burkart P, Spaich C, Meng M, Holthausen H, Adès L, Seidel J, Mangold E, Buyse G, Meinecke P, Schara U, Zeschnigk C, Muller D, Helland G, Schulze B, Wright ML, Kortge-Jung S, Hehr A, Bogdahn U, Schuierer G, Kohlhase J, Aigner L, Wolff G, Hehr U, Winkler J. Location and type of mutation in the LIS1 gene do not predict phenotypic severity. Neurology. 2007 Jul 31;69(5):442-7.

Yis U, Uyanik G, Kurul S, Dirik E, Ozer E, Gross CHehr UA case of Walker-Warburg syndrome resulting from a homozygous POMT1 mutation. Eur J Paediatr Neurol. 2007 Jan;11(1):46-9.

Uyanik G, Elcioglu N, Penzien J, Gross C, Yilmaz Y, Olmez A, Demir E, Wahl D, Scheglmann K, Winner B, Bogdahn U, Topaloglu H, Hehr U, Winkler J. Novel truncating and missense mutations of the KCC3 gene associated with Andermann syndrome. Neurology. 2006 Apr 11;66(7):1044-8. Erratum in: Neurology. 2006 Oct 24;67(8):1528.

Hehr UHehr A, Uyanik G, Phelan E, Winkler J, Reardon W. A filamin A splice mutation resulting in a syndrome of facial dysmorphism, periventricular nodular heterotopia, and severe constipation reminiscent of cerebro-fronto-facial syndrome. J Med Genet. 2006 Jun;43(6):541-4. Epub 2005 Nov 18.

Haliloglu G, Gross C, Senbil N, Talim B, Hehr U, Uyanik G, Winkler J, Topaloglu H. Clinical spectrum of muscle-eye-brain disease: from the typical presentation to severe autistic features. Acta Myol. 2004 Dec;23(3):137-9.

Balci B, Uyanik G, Dincer P, Gross C, Willer T, Talim B, Haliloglu G, Kale G, Hehr U, Winkler J, Topaloğlu H. An autosomal recessive limb girdle muscular dystrophy (LGMD2) with mild mental retardation is allelic to Walker-Warburg syndrome (WWS) caused by a mutation in the POMT1 gene. Neuromuscul Disord. 2005 Apr;15(4):271-5.

Meyer S, Struffert T, Uyanik G, Oehl-Jaschkowitz B, Hehr U, Shamdeen MG. [Congenital muscular dystrophies: muscle-eye-brain disease]. Klin Padiatr. 2005 Mar-Apr;217(2):68-9. German. 

Wohlrab G, Uyanik G, Gross CHehr U, Winkler J, Schmitt B, Boltshauser E. Familial West syndrome and dystonia caused by an Aristaless related homeobox gene mutation. Eur J Pediatr. 2005 May;164(5):326-8.

Hahn A, Gross C, Uyanik G, Hehr U, Hügens-Penzel M, Alzen G, Neubauer BA. X-linked lissencephaly with abnormal genitalia associated with renal phosphate wasting. Neuropediatrics. 2004 Jun;35(3):202-5.

Hartmann H, Uyanik G, Gross CHehr U, Lücke T, Arslan-Kirchner M, Antosch B, Das AM, Winkler J. Agenesis of the corpus callosum, abnormal genitalia and intractable epilepsy due to a novel familial mutation in the Aristaless-related homeobox gene. Neuropediatrics. 2004 Jun;35(3):157-60.

Hehr UGross C, Diebold U, Wahl D, Beudt U, Heidemann P, Hehr A, Mueller D. Wide phenotypic variability in families with holoprosencephaly and a sonic hedgehog mutation. Eur J Pediatr. 2004 Jul;163(7):347-52.

Martin P, Uyanik G, Wiemer-Kruel A, Schneider S, Gross CHehr U, Winkler J. Different clinical and morphological phenotypes in monozygotic twins with identical DCX mutation. J Neurol. 2004 Jan;251(1):108-10.

Uyanik G, Aigner L, Martin P, Gross C, Neumann D, Marschner-Schäfer H, Hehr U, Winkler J. ARX mutations in X-linked lissencephaly with abnormal genitalia. Neurology. 2003 Jul 22;61(2):232-5.

Wallis DE, Roessler E, Hehr U, Nanni L, Wiltshire T, Richieri-Costa A, Gillessen-Kaesbach G, Zackai EH, Rommens J, Muenke M. Mutations in the homeodomain of the human SIX3 gene cause holoprosencephaly. Nat Genet. 1999 Jun;22(2):196-8.

Schell U, Wienberg J, Köhler A, Bray-Ward P, Ward DE, Wilson WG, Allen WP, Lebel RR, Sawyer JR, Campbell PL, Aughton DJ, Punnett HH, Lammer EJ, Kao FT, Ward DC, Muenke M. Molecular characterization of breakpoints in patients with holoprosencephaly and definition of the HPE2 critical region 2p21. Hum Mol Genet. 1996 Feb;5(2):223-9.