Novel variants in KAT6B spectrum of disorders expand our knowledge of clinical manifestations and molecular mechanisms
Abstract The phenotypic variability associated with pathogenic variants in Lysine Acetyltransferase 6B (KAT6B, a.k.a. MORF, MYST4) results in several interrelated syndromes including Say‐Barber‐Biesecker‐Young‐Simpson Syndrome and Genitopatellar Syndrome. Here we present 20 new cases representing 10...
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2021
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oai:doaj.org-article:beed8cf5cfdc460cbcfd56990a49d6fd2021-11-10T16:39:24ZNovel variants in KAT6B spectrum of disorders expand our knowledge of clinical manifestations and molecular mechanisms2324-926910.1002/mgg3.1809https://doaj.org/article/beed8cf5cfdc460cbcfd56990a49d6fd2021-10-01T00:00:00Zhttps://doi.org/10.1002/mgg3.1809https://doaj.org/toc/2324-9269Abstract The phenotypic variability associated with pathogenic variants in Lysine Acetyltransferase 6B (KAT6B, a.k.a. MORF, MYST4) results in several interrelated syndromes including Say‐Barber‐Biesecker‐Young‐Simpson Syndrome and Genitopatellar Syndrome. Here we present 20 new cases representing 10 novel KAT6B variants. These patients exhibit a range of clinical phenotypes including intellectual disability, mobility and language difficulties, craniofacial dysmorphology, and skeletal anomalies. Given the range of features previously described for KAT6B‐related syndromes, we have identified additional phenotypes including concern for keratoconus, sensitivity to light or noise, recurring infections, and fractures in greater numbers than previously reported. We surveyed clinicians to qualitatively assess the ways families engage with genetic counselors upon diagnosis. We found that 56% (10/18) of individuals receive diagnoses before the age of 2 years (median age = 1.96 years), making it challenging to address future complications with limited accessible information and vast phenotypic severity. We used CRISPR to introduce truncating variants into the KAT6B gene in model cell lines and performed chromatin accessibility and transcriptome sequencing to identify key dysregulated pathways. This study expands the clinical spectrum and addresses the challenges to management and genetic counseling for patients with KAT6B‐related disorders.Megan YabumotoJessica KianmahdMeghna SinghMaria F. PalafoxAngela WeiKathryn ElliottDana H. GoodloeS. Joy DeanCatherine GoochBrianna K. MurrayErin SwartzSamantha A. Schrier VerganoMeghan C. TowneKimberly NugentElizabeth R. RoederChristina KresgeBeth A. PletcherKatheryn GrandJohn M. Graham Jr.Ryan GatesNatalia Gomez‐OspinaSubhadra RamanathanRobin Dawn ClarkKimberly GlaserPaul J. BenkeJulie S. CohenAli FatemiWeiyi MuKristin W. BarananoJill A. MaddenCynthia S. GubbelsTimothy W. YuPankaj B. AgrawalMary‐Kathryn ChambersChanika PhornphutkulJohn A. PughKate A. TauberSvetlana AzovaJessica R. SmithAnne O’Donnell‐LuriaHannah MedskerSiddharth SrivastavaDeborah KrakowDaniela N. SchweitzerValerie A. ArboledaWileyarticleCRISPRGenitopatellar syndromeKAT6B‐related disordersphenotypic spectrumSay‐Barber‐Biesecker‐Young‐Simpson syndromevariable expressivity, rare genetic diagnosisGeneticsQH426-470ENMolecular Genetics & Genomic Medicine, Vol 9, Iss 10, Pp n/a-n/a (2021) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
CRISPR Genitopatellar syndrome KAT6B‐related disorders phenotypic spectrum Say‐Barber‐Biesecker‐Young‐Simpson syndrome variable expressivity, rare genetic diagnosis Genetics QH426-470 |
| spellingShingle |
CRISPR Genitopatellar syndrome KAT6B‐related disorders phenotypic spectrum Say‐Barber‐Biesecker‐Young‐Simpson syndrome variable expressivity, rare genetic diagnosis Genetics QH426-470 Megan Yabumoto Jessica Kianmahd Meghna Singh Maria F. Palafox Angela Wei Kathryn Elliott Dana H. Goodloe S. Joy Dean Catherine Gooch Brianna K. Murray Erin Swartz Samantha A. Schrier Vergano Meghan C. Towne Kimberly Nugent Elizabeth R. Roeder Christina Kresge Beth A. Pletcher Katheryn Grand John M. Graham Jr. Ryan Gates Natalia Gomez‐Ospina Subhadra Ramanathan Robin Dawn Clark Kimberly Glaser Paul J. Benke Julie S. Cohen Ali Fatemi Weiyi Mu Kristin W. Baranano Jill A. Madden Cynthia S. Gubbels Timothy W. Yu Pankaj B. Agrawal Mary‐Kathryn Chambers Chanika Phornphutkul John A. Pugh Kate A. Tauber Svetlana Azova Jessica R. Smith Anne O’Donnell‐Luria Hannah Medsker Siddharth Srivastava Deborah Krakow Daniela N. Schweitzer Valerie A. Arboleda Novel variants in KAT6B spectrum of disorders expand our knowledge of clinical manifestations and molecular mechanisms |
| description |
Abstract The phenotypic variability associated with pathogenic variants in Lysine Acetyltransferase 6B (KAT6B, a.k.a. MORF, MYST4) results in several interrelated syndromes including Say‐Barber‐Biesecker‐Young‐Simpson Syndrome and Genitopatellar Syndrome. Here we present 20 new cases representing 10 novel KAT6B variants. These patients exhibit a range of clinical phenotypes including intellectual disability, mobility and language difficulties, craniofacial dysmorphology, and skeletal anomalies. Given the range of features previously described for KAT6B‐related syndromes, we have identified additional phenotypes including concern for keratoconus, sensitivity to light or noise, recurring infections, and fractures in greater numbers than previously reported. We surveyed clinicians to qualitatively assess the ways families engage with genetic counselors upon diagnosis. We found that 56% (10/18) of individuals receive diagnoses before the age of 2 years (median age = 1.96 years), making it challenging to address future complications with limited accessible information and vast phenotypic severity. We used CRISPR to introduce truncating variants into the KAT6B gene in model cell lines and performed chromatin accessibility and transcriptome sequencing to identify key dysregulated pathways. This study expands the clinical spectrum and addresses the challenges to management and genetic counseling for patients with KAT6B‐related disorders. |
| format |
article |
| author |
Megan Yabumoto Jessica Kianmahd Meghna Singh Maria F. Palafox Angela Wei Kathryn Elliott Dana H. Goodloe S. Joy Dean Catherine Gooch Brianna K. Murray Erin Swartz Samantha A. Schrier Vergano Meghan C. Towne Kimberly Nugent Elizabeth R. Roeder Christina Kresge Beth A. Pletcher Katheryn Grand John M. Graham Jr. Ryan Gates Natalia Gomez‐Ospina Subhadra Ramanathan Robin Dawn Clark Kimberly Glaser Paul J. Benke Julie S. Cohen Ali Fatemi Weiyi Mu Kristin W. Baranano Jill A. Madden Cynthia S. Gubbels Timothy W. Yu Pankaj B. Agrawal Mary‐Kathryn Chambers Chanika Phornphutkul John A. Pugh Kate A. Tauber Svetlana Azova Jessica R. Smith Anne O’Donnell‐Luria Hannah Medsker Siddharth Srivastava Deborah Krakow Daniela N. Schweitzer Valerie A. Arboleda |
| author_facet |
Megan Yabumoto Jessica Kianmahd Meghna Singh Maria F. Palafox Angela Wei Kathryn Elliott Dana H. Goodloe S. Joy Dean Catherine Gooch Brianna K. Murray Erin Swartz Samantha A. Schrier Vergano Meghan C. Towne Kimberly Nugent Elizabeth R. Roeder Christina Kresge Beth A. Pletcher Katheryn Grand John M. Graham Jr. Ryan Gates Natalia Gomez‐Ospina Subhadra Ramanathan Robin Dawn Clark Kimberly Glaser Paul J. Benke Julie S. Cohen Ali Fatemi Weiyi Mu Kristin W. Baranano Jill A. Madden Cynthia S. Gubbels Timothy W. Yu Pankaj B. Agrawal Mary‐Kathryn Chambers Chanika Phornphutkul John A. Pugh Kate A. Tauber Svetlana Azova Jessica R. Smith Anne O’Donnell‐Luria Hannah Medsker Siddharth Srivastava Deborah Krakow Daniela N. Schweitzer Valerie A. Arboleda |
| author_sort |
Megan Yabumoto |
| title |
Novel variants in KAT6B spectrum of disorders expand our knowledge of clinical manifestations and molecular mechanisms |
| title_short |
Novel variants in KAT6B spectrum of disorders expand our knowledge of clinical manifestations and molecular mechanisms |
| title_full |
Novel variants in KAT6B spectrum of disorders expand our knowledge of clinical manifestations and molecular mechanisms |
| title_fullStr |
Novel variants in KAT6B spectrum of disorders expand our knowledge of clinical manifestations and molecular mechanisms |
| title_full_unstemmed |
Novel variants in KAT6B spectrum of disorders expand our knowledge of clinical manifestations and molecular mechanisms |
| title_sort |
novel variants in kat6b spectrum of disorders expand our knowledge of clinical manifestations and molecular mechanisms |
| publisher |
Wiley |
| publishDate |
2021 |
| url |
https://doaj.org/article/beed8cf5cfdc460cbcfd56990a49d6fd |
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