Loss of Protocadherin‐12 L eads to D iencephalic‐ M esencephalic J unction D ysplasia S yndrome
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...
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| Published in | Annals of neurology Vol. 84; no. 5; pp. 638 - 647 |
|---|---|
| Main Authors | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
01.11.2018
|
| Online Access | Get full text |
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| 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;84:638–647 |
|---|---|
| AbstractList | 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;84:638–647 |
| Author | Issa, Mahmoud Y. Gumus, Hakan Shomron, Noam McEvoy‐Venneri, Jennifer Rosti, Rasim Ozgur Silhavy, Jennifer L. Pillar, Nir Kumandas, Sefer Heimer, Gali Yasuno, Katsuhito Akizu, Naiara Erson‐Omay, Emine Z. Ben‐Zeev, Bruria Lewis, Steven M. Copeland, Brett Schroth, Jana Fang, Rebecca Per, Huseyin Porat, Yuval Gabriel, Stacey Saleem, Sahar N. Guemez‐Gamboa, Alicia Musaev, Damir Akgumus, Gozde Tugce Gregor, Anne Bayram, Ayse Kacar Bilguvar, Kaya Çağlayan, Ahmet Okay Stanley, Valentina Gunel, Murat Weissglas‐Volkov, Daphna Gleeson, Joseph G. Belandres, Denice Einhorn, Yaron Zaki, Maha S. |
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Radiology Department‐Faculty of Medicine Cairo University Cairo Egypt – sequence: 7 givenname: Damir surname: Musaev fullname: Musaev, Damir organization: Department of Neurosciences University of California San Diego, La Jolla CA – sequence: 8 givenname: Jennifer surname: McEvoy‐Venneri fullname: McEvoy‐Venneri, Jennifer organization: Department of Neurosciences University of California San Diego, La Jolla CA – sequence: 9 givenname: Denice surname: Belandres fullname: Belandres, Denice organization: Department of Neurosciences University of California San Diego, La Jolla CA – sequence: 10 givenname: Naiara surname: Akizu fullname: Akizu, Naiara organization: Department of Neurosciences University of California San Diego, La Jolla CA – sequence: 11 givenname: Jennifer L. surname: Silhavy fullname: Silhavy, Jennifer L. organization: Department of Neurosciences University of California San Diego, La Jolla CA – sequence: 12 givenname: Jana surname: Schroth fullname: Schroth, Jana organization: Department of Neurosciences University of California San Diego, La Jolla CA – sequence: 13 givenname: Rasim Ozgur surname: Rosti fullname: Rosti, Rasim Ozgur organization: Howard Hughes Medical Institute, Laboratory for Pediatric Brain Disease Rockefeller University New York NY – sequence: 14 givenname: Brett surname: Copeland fullname: Copeland, Brett organization: Howard Hughes Medical Institute, Laboratory for Pediatric Brain Disease Rockefeller University New York NY – sequence: 15 givenname: Steven M. surname: Lewis fullname: Lewis, Steven M. organization: Howard Hughes Medical Institute, Laboratory for Pediatric Brain Disease Rockefeller University New York NY – sequence: 16 givenname: Rebecca surname: Fang fullname: Fang, Rebecca organization: Howard Hughes Medical Institute, Laboratory for Pediatric Brain Disease Rockefeller University New York NY – sequence: 17 givenname: Mahmoud Y. surname: Issa fullname: Issa, Mahmoud Y. organization: Department of Clinical Genetics National Research Centre Cairo Egypt – sequence: 18 givenname: Huseyin surname: Per fullname: Per, Huseyin organization: Department of Paediatrics, Division of Paediatric Neurology, School of Medicine Erciyes University Kayseri Turkey – sequence: 19 givenname: Hakan surname: Gumus fullname: Gumus, Hakan organization: Department of Paediatrics, Division of Paediatric Neurology, School of Medicine Erciyes University Kayseri Turkey – sequence: 20 givenname: Ayse Kacar surname: Bayram fullname: Bayram, Ayse Kacar organization: Department of Paediatrics, Division of Paediatric Neurology, School of Medicine Erciyes University Kayseri Turkey – sequence: 21 givenname: Sefer surname: Kumandas fullname: Kumandas, Sefer organization: Department of Paediatrics, Division of Paediatric Neurology, School of Medicine Erciyes University Kayseri Turkey – sequence: 22 givenname: Gozde Tugce surname: Akgumus fullname: Akgumus, Gozde Tugce organization: Departments of Neurosurgery Neurobiology and Genetics, Yale School of Medicine New Haven CT – sequence: 23 givenname: Emine Z. surname: Erson‐Omay fullname: Erson‐Omay, Emine Z. organization: Departments of Neurosurgery Neurobiology and Genetics, Yale School of Medicine New Haven CT – sequence: 24 givenname: Katsuhito surname: Yasuno fullname: Yasuno, Katsuhito organization: Departments of Neurosurgery Neurobiology and Genetics, Yale School of Medicine New Haven CT – sequence: 25 givenname: Kaya surname: Bilguvar fullname: Bilguvar, Kaya organization: Departments of Neurosurgery Neurobiology and Genetics, Yale School of Medicine New Haven CT – sequence: 26 givenname: Gali surname: Heimer fullname: Heimer, Gali organization: Sackler School of Medicine Tel Aviv University Tel Aviv Israel – sequence: 27 givenname: Nir surname: Pillar fullname: Pillar, Nir organization: Sackler School of Medicine Tel Aviv University Tel Aviv Israel – sequence: 28 givenname: Noam surname: Shomron fullname: Shomron, Noam organization: Sackler School of Medicine Tel Aviv University Tel Aviv Israel – sequence: 29 givenname: Daphna surname: Weissglas‐Volkov fullname: Weissglas‐Volkov, Daphna organization: Sackler School of Medicine Tel Aviv University Tel Aviv Israel – sequence: 30 givenname: Yuval surname: Porat fullname: Porat, Yuval organization: Genoox Tel Aviv Israel – sequence: 31 givenname: Yaron surname: Einhorn fullname: Einhorn, Yaron organization: Genoox Tel Aviv Israel – sequence: 32 givenname: Stacey surname: Gabriel fullname: Gabriel, Stacey organization: Broad Institute of Harvard and Massachusetts Institute of Technology Cambridge MA – sequence: 33 givenname: Bruria surname: Ben‐Zeev fullname: Ben‐Zeev, Bruria organization: Sackler School of Medicine Tel Aviv University Tel Aviv Israel – sequence: 34 givenname: Murat surname: Gunel fullname: Gunel, Murat organization: Department of Neurosurgery Yale School of Medicine New Haven CT – sequence: 35 givenname: Joseph G. orcidid: 0000-0002-0889-9220 surname: Gleeson fullname: Gleeson, Joseph G. organization: Howard Hughes Medical Institute, Laboratory for Pediatric Brain Disease Rockefeller University New York NY, Department of Neurosciences University of California San Diego, La Jolla CA |
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| References | e_1_2_8_28_1 e_1_2_8_29_1 e_1_2_8_24_1 e_1_2_8_25_1 e_1_2_8_26_1 Madry J (e_1_2_8_5_1) 2017; 17 e_1_2_8_27_1 e_1_2_8_3_1 e_1_2_8_2_1 e_1_2_8_4_1 e_1_2_8_7_1 e_1_2_8_6_1 e_1_2_8_9_1 e_1_2_8_8_1 e_1_2_8_20_1 e_1_2_8_21_1 e_1_2_8_22_1 e_1_2_8_23_1 e_1_2_8_17_1 e_1_2_8_18_1 e_1_2_8_19_1 e_1_2_8_13_1 e_1_2_8_36_1 e_1_2_8_14_1 e_1_2_8_35_1 e_1_2_8_15_1 e_1_2_8_16_1 e_1_2_8_37_1 e_1_2_8_32_1 e_1_2_8_10_1 e_1_2_8_31_1 e_1_2_8_11_1 e_1_2_8_34_1 e_1_2_8_12_1 e_1_2_8_33_1 e_1_2_8_30_1 |
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| Snippet | Objective
To identify causes of the autosomal‐recessive malformation, diencephalic‐mesencephalic junction dysplasia (DMJD) syndrome.
Methods
Eight families... |
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