Unusual 4p16.3 deletions suggest an additional chromosome region for the Wolf-Hirschhorn syndrome-associated seizures disorder.

[wolf-hirschhorn syndrome]

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 4 p chromosome regions where genes for seizures reside .Comparison of our three unusual 4 p 16 .3 deletions with 13 literature reports . Array-comparative genomic hybridization (a-CGH ). Real-time polymerase chain reaction (RT-PCR ) on messanger RNA (mRNA ) of LETM 1 and CPLX 1 . Direct sequencing of LETM 1 .Three unusual 4 p 16 .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 4 p deletions preserving LETM 1 had seizures , whereas seven of seven with interstitial deletions including LETM 1 and preserving the terminal 1 Mb region on 4 p did not . An additional chromosome region for seizures is suggested , falling within the terminal 1 .5 Mb on 4 p , not including LETM 1 .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 4 p , most likely distal to LETM 1 . A PowerPoint slide summarizing this article is available for download in the Supporting Information section here .

Diseases
Validation

Diseases presenting "seizures" symptom

alexander disease

alpha-thalassemia

cadasil

canavan disease

child syndrome

classical phenylketonuria

coats disease

cohen syndrome

cowden syndrome

erdheim-chester disease

familial hypocalciuric hypercalcemia

familial mediterranean fever

gm1 gangliosidosis

hirschsprung disease

homocystinuria without methylmalonic aciduria

kabuki syndrome

kallmann syndrome

krabbe disease

lamellar ichthyosis

legionellosis

locked-in syndrome

lymphangioleiomyomatosis

malignant atrophic papulosis

monosomy 21

neonatal adrenoleukodystrophy

oligodontia

phenylketonuria

proteus syndrome

pyruvate dehydrogenase deficiency

scrub typhus

sneddon syndrome

wolf-hirschhorn syndrome

x-linked adrenoleukodystrophy

zellweger syndrome

This symptom has already been validated