Loss of Protocadherin-12 Leads to Diencephalic-Mesencephalic Junction Dysplasia Syndrome

Alicia Dione Guemez Gamboa; Ahmet Okay Çağlayan; Valentina Stanley; Anne Gregor; Maha S. Zaki; Sahar N. Saleem; Damir Musaev; Jennifer McEvoy-Venneri; Denice Belandres; Naiara Akizu; Jennifer L. Silhavy; Jana Schroth; Rasim Ozgur Rosti; Brett Copeland; Steven M. Lewis; Rebecca Fang; Mahmoud Y. Issa; Huseyin Per; Hakan Gumus; Ayse Kacar Bayram; Sefer Kumandas; Gozde Tugce Akgumus; Emine Z. Erson-Omay; Katsuhito Yasuno; Kaya Bilguvar; Gali Heimer; Nir Pillar; Noam Shomron; Daphna Weissglas-Volkov; Yuval Porat; Yaron Einhorn; Stacey Gabriel; Bruria Ben-Zeev; Murat Gunel; Joseph G. Gleeson

doi:10.1002/ana.25327

Loss of Protocadherin-12 Leads to Diencephalic-Mesencephalic Junction Dysplasia Syndrome

Alicia Dione Guemez Gamboa, Ahmet Okay Çağlayan, Valentina Stanley, Anne Gregor, Maha S. Zaki, Sahar N. Saleem, Damir Musaev, Jennifer McEvoy-Venneri, Denice Belandres, Naiara Akizu, Jennifer L. Silhavy, Jana Schroth, Rasim Ozgur Rosti, Brett Copeland, Steven M. Lewis, Rebecca Fang, Mahmoud Y. Issa, Huseyin Per, Hakan Gumus, Ayse Kacar BayramSefer Kumandas, Gozde Tugce Akgumus, Emine Z. Erson-Omay, Katsuhito Yasuno, Kaya Bilguvar, Gali Heimer, Nir Pillar, Noam Shomron, Daphna Weissglas-Volkov, Yuval Porat, Yaron Einhorn, Stacey Gabriel, Bruria Ben-Zeev, Murat Gunel, Joseph G. Gleeson^*

^*Corresponding author for this work

Neuroscience

Research output: Contribution to journal › Article › peer-review

22 Scopus citations

Abstract

Objective: To identify causes of the autosomal-recessive malformation, diencephalic-mesencephalic junction dysplasia (DMJD) syndrome. Methods: Eight families with DMJD were studied by whole-exome or targeted sequencing, with detailed clinical and radiological characterization. Patient-derived induced pluripotent stem cells were derived into neural precursor and endothelial cells to study gene expression. Results: All patients showed biallelic mutations in the nonclustered protocadherin-12 (PCDH12) gene. The characteristic clinical presentation included progressive microcephaly, craniofacial dysmorphism, psychomotor disability, epilepsy, and axial hypotonia with variable appendicular spasticity. Brain imaging showed brainstem malformations and with frequent thinned corpus callosum with punctate brain calcifications, reflecting expression of PCDH12 in neural and endothelial cells. These cells showed lack of PCDH12 expression and impaired neurite outgrowth. Interpretation: DMJD patients have biallelic mutations in PCDH12 and lack of protein expression. These patients present with characteristic microcephaly and abnormalities of white matter tracts. Such pathogenic variants predict a poor outcome as a result of brainstem malformation and evidence of white matter tract defects, and should be added to the phenotypic spectrum associated with PCDH12-related conditions. Ann Neurol 2018;84:646–655.

Original language	English (US)
Pages (from-to)	638-647
Number of pages	10
Journal	Annals of neurology
Volume	84
Issue number	5
DOIs	https://doi.org/10.1002/ana.25327
State	Published - Nov 2018

Funding

This work was supported by the NIH R01NS048453 and R01NS098004 to J.G.G., P30NS047101 for imaging support, K99NS089943 to A.G.-G., the Yale Center for Mendelian Disorders U54HG006504, RC2NS070477, and the Gregory M. Kiez and Mehmet Kutman Foundation to M.G., Simons Foundation Grants 175303 and 275275, QNRF grant NPRP 6-1463-3-351 to J.G.G. and T.B.-O., and UM1 HG008900 to the Broad Institute of MIT and Harvard Center for Mendelian Genomics (Broad CMG). We acknowledge the Yale Biomedical High-Performance Computing Center for data analysis and storage; the Yale Program on Neurogenetics and the Yale Center for Human Genetics and Genomics; the Center for Inherited Disease Research for genotyping; and the Simons Foundation Autism Research Initiative. Sequencing was provided, in part, by a gift from BGI and Illumina, Inc., to Rady Children's Hospital, San Diego for undiagnosed patients. Consortium for Autosomal Recessive Intellectual Disability (CARID) supported patient ascertainment. This work was supported by the NIH R01NS048453 and R01NS098004 to J.G.G., P30NS047101 for imaging support, K99NS089943 to A.G.-G., the Yale Center for Mendelian Disorders U54HG006504, RC2NS070477, and the Gregory M. Kiez and Mehmet Kutman Foundation to M.G., Simons Foundation Grants 175303 and 275275, QNRF grant NPRP 6-1463-3-351 to J.G.G. and T.B.-O., and UM1 HG008900 to the Broad Institute of MIT and Harvard Center for Mendelian Genomics (Broad CMG).

ASJC Scopus subject areas

Neurology
Clinical Neurology

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10.1002/ana.25327

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Guemez Gamboa, A. D., Çağlayan, A. O., Stanley, V., Gregor, A., Zaki, M. S., Saleem, S. N., Musaev, D., McEvoy-Venneri, J., Belandres, D., Akizu, N., Silhavy, J. L., Schroth, J., Rosti, R. O., Copeland, B., Lewis, S. M., Fang, R., Issa, M. Y., Per, H., Gumus, H., ... Gleeson, J. G. (2018). Loss of Protocadherin-12 Leads to Diencephalic-Mesencephalic Junction Dysplasia Syndrome. Annals of neurology, 84(5), 638-647. https://doi.org/10.1002/ana.25327

@article{da77735c7db14c5f928c6e636b4647e0,

title = "Loss of Protocadherin-12 Leads to Diencephalic-Mesencephalic Junction Dysplasia Syndrome",

abstract = "Objective: To identify causes of the autosomal-recessive malformation, diencephalic-mesencephalic junction dysplasia (DMJD) syndrome. Methods: Eight families with DMJD were studied by whole-exome or targeted sequencing, with detailed clinical and radiological characterization. Patient-derived induced pluripotent stem cells were derived into neural precursor and endothelial cells to study gene expression. Results: All patients showed biallelic mutations in the nonclustered protocadherin-12 (PCDH12) gene. The characteristic clinical presentation included progressive microcephaly, craniofacial dysmorphism, psychomotor disability, epilepsy, and axial hypotonia with variable appendicular spasticity. Brain imaging showed brainstem malformations and with frequent thinned corpus callosum with punctate brain calcifications, reflecting expression of PCDH12 in neural and endothelial cells. These cells showed lack of PCDH12 expression and impaired neurite outgrowth. Interpretation: DMJD patients have biallelic mutations in PCDH12 and lack of protein expression. These patients present with characteristic microcephaly and abnormalities of white matter tracts. Such pathogenic variants predict a poor outcome as a result of brainstem malformation and evidence of white matter tract defects, and should be added to the phenotypic spectrum associated with PCDH12-related conditions. Ann Neurol 2018;84:646–655.",

author = "{Guemez Gamboa}, {Alicia Dione} and {\c C}ağlayan, {Ahmet Okay} and Valentina Stanley and Anne Gregor and Zaki, {Maha S.} and Saleem, {Sahar N.} and Damir Musaev and Jennifer McEvoy-Venneri and Denice Belandres and Naiara Akizu and Silhavy, {Jennifer L.} and Jana Schroth and Rosti, {Rasim Ozgur} and Brett Copeland and Lewis, {Steven M.} and Rebecca Fang and Issa, {Mahmoud Y.} and Huseyin Per and Hakan Gumus and Bayram, {Ayse Kacar} and Sefer Kumandas and Akgumus, {Gozde Tugce} and Erson-Omay, {Emine Z.} and Katsuhito Yasuno and Kaya Bilguvar and Gali Heimer and Nir Pillar and Noam Shomron and Daphna Weissglas-Volkov and Yuval Porat and Yaron Einhorn and Stacey Gabriel and Bruria Ben-Zeev and Murat Gunel and Gleeson, {Joseph G.}",

note = "Publisher Copyright: {\textcopyright} 2018 American Neurological Association",

year = "2018",

month = nov,

doi = "10.1002/ana.25327",

language = "English (US)",

volume = "84",

pages = "638--647",

journal = "Annals of neurology",

issn = "0364-5134",

publisher = "John Wiley & Sons Inc.",

number = "5",

}

Guemez Gamboa, AD, Çağlayan, AO, Stanley, V, Gregor, A, Zaki, MS, Saleem, SN, Musaev, D, McEvoy-Venneri, J, Belandres, D, Akizu, N, Silhavy, JL, Schroth, J, Rosti, RO, Copeland, B, Lewis, SM, Fang, R, Issa, MY, Per, H, Gumus, H, Bayram, AK, Kumandas, S, Akgumus, GT, Erson-Omay, EZ, Yasuno, K, Bilguvar, K, Heimer, G, Pillar, N, Shomron, N, Weissglas-Volkov, D, Porat, Y, Einhorn, Y, Gabriel, S, Ben-Zeev, B, Gunel, M & Gleeson, JG 2018, 'Loss of Protocadherin-12 Leads to Diencephalic-Mesencephalic Junction Dysplasia Syndrome', Annals of neurology, vol. 84, no. 5, pp. 638-647. https://doi.org/10.1002/ana.25327

TY - JOUR

T1 - Loss of Protocadherin-12 Leads to Diencephalic-Mesencephalic Junction Dysplasia Syndrome

AU - Guemez Gamboa, Alicia Dione

AU - Çağlayan, Ahmet Okay

AU - Stanley, Valentina

AU - Gregor, Anne

AU - Zaki, Maha S.

AU - Saleem, Sahar N.

AU - Musaev, Damir

AU - McEvoy-Venneri, Jennifer

AU - Belandres, Denice

AU - Akizu, Naiara

AU - Silhavy, Jennifer L.

AU - Schroth, Jana

AU - Rosti, Rasim Ozgur

AU - Copeland, Brett

AU - Lewis, Steven M.

AU - Fang, Rebecca

AU - Issa, Mahmoud Y.

AU - Per, Huseyin

AU - Gumus, Hakan

AU - Bayram, Ayse Kacar

AU - Kumandas, Sefer

AU - Akgumus, Gozde Tugce

AU - Erson-Omay, Emine Z.

AU - Yasuno, Katsuhito

AU - Bilguvar, Kaya

AU - Heimer, Gali

AU - Pillar, Nir

AU - Shomron, Noam

AU - Weissglas-Volkov, Daphna

AU - Porat, Yuval

AU - Einhorn, Yaron

AU - Gabriel, Stacey

AU - Ben-Zeev, Bruria

AU - Gunel, Murat

AU - Gleeson, Joseph G.

PY - 2018/11

Y1 - 2018/11

N2 - Objective: To identify causes of the autosomal-recessive malformation, diencephalic-mesencephalic junction dysplasia (DMJD) syndrome. Methods: Eight families with DMJD were studied by whole-exome or targeted sequencing, with detailed clinical and radiological characterization. Patient-derived induced pluripotent stem cells were derived into neural precursor and endothelial cells to study gene expression. Results: All patients showed biallelic mutations in the nonclustered protocadherin-12 (PCDH12) gene. The characteristic clinical presentation included progressive microcephaly, craniofacial dysmorphism, psychomotor disability, epilepsy, and axial hypotonia with variable appendicular spasticity. Brain imaging showed brainstem malformations and with frequent thinned corpus callosum with punctate brain calcifications, reflecting expression of PCDH12 in neural and endothelial cells. These cells showed lack of PCDH12 expression and impaired neurite outgrowth. Interpretation: DMJD patients have biallelic mutations in PCDH12 and lack of protein expression. These patients present with characteristic microcephaly and abnormalities of white matter tracts. Such pathogenic variants predict a poor outcome as a result of brainstem malformation and evidence of white matter tract defects, and should be added to the phenotypic spectrum associated with PCDH12-related conditions. Ann Neurol 2018;84:646–655.

AB - Objective: To identify causes of the autosomal-recessive malformation, diencephalic-mesencephalic junction dysplasia (DMJD) syndrome. Methods: Eight families with DMJD were studied by whole-exome or targeted sequencing, with detailed clinical and radiological characterization. Patient-derived induced pluripotent stem cells were derived into neural precursor and endothelial cells to study gene expression. Results: All patients showed biallelic mutations in the nonclustered protocadherin-12 (PCDH12) gene. The characteristic clinical presentation included progressive microcephaly, craniofacial dysmorphism, psychomotor disability, epilepsy, and axial hypotonia with variable appendicular spasticity. Brain imaging showed brainstem malformations and with frequent thinned corpus callosum with punctate brain calcifications, reflecting expression of PCDH12 in neural and endothelial cells. These cells showed lack of PCDH12 expression and impaired neurite outgrowth. Interpretation: DMJD patients have biallelic mutations in PCDH12 and lack of protein expression. These patients present with characteristic microcephaly and abnormalities of white matter tracts. Such pathogenic variants predict a poor outcome as a result of brainstem malformation and evidence of white matter tract defects, and should be added to the phenotypic spectrum associated with PCDH12-related conditions. Ann Neurol 2018;84:646–655.

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U2 - 10.1002/ana.25327

DO - 10.1002/ana.25327

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AN - SCOPUS:85054513921

SN - 0364-5134

VL - 84

SP - 638

EP - 647

JO - Annals of neurology

JF - Annals of neurology

IS - 5

ER -

Loss of Protocadherin-12 Leads to Diencephalic-Mesencephalic Junction Dysplasia Syndrome

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