ZTTK syndrome: Difference between revisions

'''ZTTK syndrome (Zhu-Tokita-Takenouchi-Kim syndrome)''' is a rare multisystem disease caused in humans by a genetic mutation of the [[SON (gene)|SON gene]]. Common symptoms include [[Developmental disability|developmental delay]] and often mildlight to severe [[intellectual disability]].<ref name=":0">{{cite journal|doi=10.1016/j.ajhg.2016.06.029|pmid=27545680|pmc=5011044|title=De Novo Mutations in SON Disrupt RNA Splicing of Genes Essential for Brain Development and Metabolism, Causing an Intellectual-Disability Syndrome|journal=The American Journal of Human Genetics|volume=99|issue=3|pages=711–719|year=2016|last1=Kim|first1=Jung-Hyun|last2=Shinde|first2=Deepali N|last3=Reijnders|first3=Margot R.F|last4=Hauser|first4=Natalie S|last5=Belmonte|first5=Rebecca L|last6=Wilson|first6=Gregory R|last7=Bosch|first7=Daniëlle G.M|last8=Bubulya|first8=Paula A|last9=Shashi|first9=Vandana|last10=Petrovski|first10=Slavé|last11=Stone|first11=Joshua K|last12=Park|first12=Eun Young|last13=Veltman|first13=Joris A|last14=Sinnema|first14=Margje|last15=Stumpel|first15=Connie T.R.M|last16=Draaisma|first16=Jos M|last17=Nicolai|first17=Joost|last18=Yntema|first18=Helger G|last19=Lindstrom|first19=Kristin|last20=De Vries|first20=Bert B.A|last21=Jewett|first21=Tamison|last22=Santoro|first22=Stephanie L|last23=Vogt|first23=Julie|last24=Bachman|first24=Kristine K|last25=Seeley|first25=Andrea H|last26=Krokosky|first26=Alyson|last27=Turner|first27=Clesson|last28=Rohena|first28=Luis|last29=Hempel|first29=Maja|last30=Kortüm|first30=Fanny|display-authors=etal}}</ref><ref name="omim">{{cite web|title=OMIM Entry # 617140 - ZTTK SYNDROME; ZTTKS|url=http://omim.org/entry/617140|website=[[Online Mendelian Inheritance in Man]]|publisher=[[Johns Hopkins University]]|access-date=27 October 2017}}</ref>

The key signs and symptoms associated with ZTTK Syndrome patients include ocular, facial and systemic features.{{cncitation needed|date=November 2020}}

ZTTK syndrome is caused by heterozygous mutations in the SON gene.<ref name=":3" /> As an [[autosomal dominant]] disease, children with parents carrying a SON mutation have a 50% risk of inheriting the mutation. However, the majority of affected individuals have [[de novo mutation]]s in the SON gene and ZTTK syndrome is not inherited to their children.<ref name=":1" />

Many individuals with ZTTK syndrome have identified [[heterozygosity]] for a de novo 4-base pair deletion<ref name=":3" /><ref>{{Cite journal|last1=Takenouchi|first1=Toshiki|last2=Miura|first2=Kiyokuni|last3=Uehara|first3=Tomoko|last4=Mizuno|first4=Seiji|last5=Kosaki|first5=Kenjiro|date=2016-06-03|title=EstablishingSONin 21q22.11 as a cause a new syndromic form of intellectual disability: Possible contribution to Braddock-Carey syndrome phenotype|journal=American Journal of Medical Genetics Part A|volume=170|issue=10|pages=2587–2590|doi=10.1002/ajmg.a.37761|pmid=27256762|issn=1552-4825|doi-access=free}}</ref> de novo mutation in [[exon]] 3 in the SON gene<ref name=":0" /> and de novo 2-base point insertion in exon,<ref name=":0" /> resulting in [[haploinsufficiency]] or a frameshift and premature termination in the [[arginine]]/[[serine]] (RS) domain. Peripheral blood cells from the sampled patients confirmed decreased levels of the mutant RNA transcript, consistent with haploinsufficiency.<ref name=":0" /> Other mutations observed include a [[nonsense mutation]], an [[in-frame deletion]] of amino acids and an entire gene deletion.<ref name=":0" /> De novo heterozygous 1-base point duplication in exon 3 and 1-base point deletion in exon 4 of the SON gene resulted in a frameshift and premature termination.<ref name=":2" /> Parental DNA has confirmed that de novo mutations are common in patients with ZTTK syndrome.<ref name=":0" /> De novo LoF mutations and haploinsufficiency for the SON gene are shown to cause profound developmental malformations during [[embryonic development]] as seen in the phenotypic manifestations of the ZTTK syndrome.<ref name=":2" />

The [[SON (gene)|SON gene]] encodes the SON protein, which is able to bind to DNA and RNA.<ref name=":5">{{Cite journal|last1=Lu|first1=Xinyi|last2=Ng|first2=Huck-Hui|last3=Bubulya|first3=Paula A.|date=2014-04-30|title=The role of SON in splicing, development, and disease|journal=Wiley Interdisciplinary Reviews: RNA|volume=5|issue=5|pages=637–646|doi=10.1002/wrna.1235|issn=1757-7004|pmc=4138235|pmid=24789761}}</ref> The SON protein is mainly localised to [[nuclear specklesspeckle]]s and involved in a variety of cellular processes such as transcription, cell cycle regulation and subnuclear organisation of pre-messenger RNA (mRNA) splicing.<ref name=":5" /><ref>{{Cite journal|last1=Spector|first1=D. L.|last2=Lamond|first2=A. I.|date=2010-10-06|title=Nuclear Speckles|journal=Cold Spring Harbor Perspectives in Biology|volume=3|issue=2|pages=a000646|doi=10.1101/cshperspect.a000646|issn=1943-0264|pmid=20926517|pmc=3039535}}</ref>

[[Whole exome sequencing]] (WES) can be used as a non-biased tool in the diagnostic evaluation of individuals with suspected genetic disorders such as the ZTTK syndrome.<ref name=":0" /> Using WES, individuals were identified with truncating variants of SON and overlapping clinical features.{{cncitation needed|date=November 2020}}

There is currently no treatment for ZTTK syndrome. However, physical therapy and addressing the specific problems of multi organ disorders may be helpful.<ref name=":1" /> The main focus should be on the diagnosis and care of individuals with ZTTK syndrome.{{cn|date=November 2020}}