Temple-Baraitser Syndrome and Zimmermann-Laband Syndrome: one clinical entity?
BACKGROUND
KCNH1 encodes a voltage-gated potassium channel that is predominantly expressed in the central nervous system. Mutations in this gene were recently found to be responsible for Temple-Baraitser Syndrome (TMBTS) and Zimmermann-Laband syndrome (ZLS).


METHODS
Here, we report a new case of TMBTS diagnosed in a Lebanese child. Whole genome sequencing was carried out on DNA samples of the proband and his parents to identify mutations associated with this disease. Sanger sequencing was performed to confirm the presence of detected variants.


RESULTS
Whole genome sequencing revealed three missense mutations in TMBTS patient: c.1042G > A in KCNH1, c.2131 T > C in STK36, and c.726C > A in ZNF517. According to all predictors, mutation in KCNH1 is damaging de novo mutation that results in substitution of Glycine by Arginine, i.e., p.(Gly348Arg). This mutation was already reported in a patient with ZLS that could affect the connecting loop between helices S4-S5 of KCNH1 with a gain of function effect.


CONCLUSIONS
Our findings demonstrate that KCNH1 mutations cause TMBTS and expand the mutational spectrum of KCNH1 in TMBTS. In addition, all cases of TMBTS were reviewed and compared to ZLS. We suggest that the two syndromes are a continuum and that the variability in the phenotypes is the result of the involvement of genetic modifiers.
Institut Jérôme Lejeune, Paris, France. andre.megarbane@yahoo.fr.
André
A
Mégarbané
Bioinformatics Division, Sidra Medical & Research Center, Doha, Qatar.
Rashid
R
Al-Ali
Institut Jérôme Lejeune, Paris, France.
Nancy
N
Choucair
Medical and Population Genetics, Broad Institute of Harvard Medical School, Boston, USA.
Monko
M
Lek
Genomics Core Laboratory, Translational Medicine Division, Sidra Medical & Research Center, Doha, Qatar.
Ena
E
Wang
Laboratory of Protein Chemistry, Weill Cornell Medicine-Qatar, Doha, Qatar.
Moncef
M
Ladjimi
POSSUMweb, Victorian Clinical Genetics Service and Murdoch Childrens Research Institute, The Royal Children's Hospital, Parkville, VIC, Australia.
Catherine M
CM
Rose
Institut Jérôme Lejeune, Paris, France.
Remy
R
Hobeika
Institut Jérôme Lejeune, Paris, France.
Yvette
Y
Macary
Bioinformatics Division, Sidra Medical & Research Center, Doha, Qatar.
Ramzi
R
Temanni
Bioinformatics Division, Sidra Medical & Research Center, Doha, Qatar.
Puthen V
PV
Jithesh
Dermatology Research Group, Translational Medicine Division, Sidra Medical & Research Center, Doha, Qatar.
Aouatef
A
Chouchane
Dermatology Research Group, Translational Medicine Division, Sidra Medical & Research Center, Doha, Qatar.
Konduru S
KS
Sastry
Laboratory of Genetic Medicine and Immunology, Weill Cornell Medicine-Qatar, Education City, Qatar Foundation, Doha, Qatar.
Remy
R
Thomas
Genomics Core Laboratory, Translational Medicine Division, Sidra Medical & Research Center, Doha, Qatar.
Sara
S
Tomei
Genomics Core Laboratory, Translational Medicine Division, Sidra Medical & Research Center, Doha, Qatar.
Wei
W
Liu
Research Office, Sidra Medical & Research Center, Doha, Qatar.
Francesco M
FM
Marincola
Medical and Population Genetics, Broad Institute of Harvard Medical School, Boston, USA.
Daniel
D
MacArthur
Laboratory of Genetic Medicine and Immunology, Weill Cornell Medicine-Qatar, Education City, Qatar Foundation, Doha, Qatar. loc2008@qatar-med.cornell.edu.
Lotfi
L
Chouchane
D000015:Abnormalities, Multiple / Q000175:diagnosis / Q000235:genetics*; D019465:Craniofacial Abnormalities / Q000175:diagnosis / Q000235:genetics*; D004247:DNA / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism; D004252:DNA Mutational Analysis; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics; D005351:Fibromatosis, Gingival / Q000175:diagnosis / Q000235:genetics*; D006214:Hallux / Q000002:abnormalities*; D006228:Hand Deformities, Congenital / Q000175:diagnosis / Q000235:genetics*; D006801:Humans; D007223:Infant; D008607:Intellectual Disability / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D020125:Mutation, Missense; D009264:Nails, Malformed / Q000175:diagnosis / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D013933:Thumb / Q000002:abnormalities* / Q000000981:diagnostic imaging; D014034:Toes / Q000000981:diagnostic imaging
D051638:Ether-A-Go-Go Potassium Channels; C496884:KCNH1 protein, human; D004247:DNA; D017346:Protein Serine-Threonine Kinases; C496588:STK36 protein, human
KCNH1; Temple-Baraitser syndrome; Whole genome sequencing; Zimmermann-Laband syndrome