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Unusual 4p16.3 deletions suggest an additional chromosome region for the Wolf‐Hirschhorn syndrome–associated seizures disorder
Author(s) -
Zollino Marcella,
Orteschi Daniela,
Ruiter Mariken,
Pfundt Rolph,
Steindl Katharina,
Cafiero Concetta,
Ricciardi Stefania,
Contaldo Ilaria,
Chieffo Daniela,
Ranalli Domiziana,
Acquafondata Celeste,
Murdolo Marina,
Marangi Giuseppe,
Asaro Alessia,
Battaglia Domenica
Publication year - 2014
Publication title -
epilepsia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.687
H-Index - 191
eISSN - 1528-1167
pISSN - 0013-9580
DOI - 10.1111/epi.12617
Subject(s) - haploinsufficiency , genetics , comparative genomic hybridization , epilepsy , biology , gene , chromosome , psychology , neuroscience , phenotype
Summary Objective Seizure disorder is one of the most relevant clinical manifestations in Wolf‐Hirschhorn syndrome ( WHS ) and it acts as independent prognostic factor for the severity of intellectual disability (ID) . LETM 1 , encoding a mitochondrial protein playing a role in K + /H + exchange and in Ca 2+ homeostasis, is currently considered the major candidate gene. However, whether haploinsufficiency limited to LETM 1 is enough to cause epilepsy is still unclear. The main purpose of the present research is to define the 4p chromosome regions where genes for seizures reside. Methods Comparison of our three unusual 4p16.3 deletions with 13 literature reports. Array‐comparative genomic hybridization (a‐CGH). Real‐time polymerase chain reaction (RT‐PCR) on messanger RNA (mRNA) of LETM1 and CPLX1 . Direct sequencing of LETM1 . Results Three unusual 4p16.3 deletions were detected by array‐ CGH in absence of a obvious clinical diagnosis of WHS . Two of these, encompassing LETM 1 , were found in subjects who never had seizures. The deletions were interstitial, spanning 1.1 Mb with preservation of the terminal 1.77 Mb region in one case and 0.84 Mb with preservation of the terminal 1.07 Mb region in the other. The other deletion was terminal, affecting a 0.564 Mb segment, with preservation of LETM 1 , and it was associated with seizures and learning difficulties. Upon evaluating our patients along with literature reports, we noted that six of eight subjects with terminal 4p deletions preserving LETM 1 had seizures, whereas seven of seven with interstitial deletions including LETM 1 and preserving the terminal 1 Mb region on 4p did not. An additional chromosome region for seizures is suggested, falling within the terminal 1.5 Mb on 4p, not including LETM 1 . Significance We consider that haploinsufficiency not limited to LETM 1 but including other genes acts as a risk factor for the WHS ‐associated seizure disorder, according to a comorbidity model of pathogenesis. Additional candidate genes reside in the terminal 1.5 Mb region on 4p, most likely distal to LETM 1 . A PowerPoint slide summarizing this article is available for download in the Supporting Information section here .