Monkol Lek, PhD
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Associate Professor Term of Genetics
Biography
Monkol received an undergraduate degree in Engineering (Computer Engineering) in 2000 at the University of New South Wales (UNSW) and then worked for IBM for 3.5 years. He returned to UNSW and completed undergraduate degrees in Science (Physiology) and Engineering (Bioinformatics) and received the University Medal in 2007. He completed his PhD (Medicine) at the University of Sydney in 2012 with the thesis topic: Functional differences between alpha-actinin-2 and alpha-actinin-3. Monkol did his post-doctoral training in Daniel MacArthur’s lab based at Massachusetts General Hospital, Harvard Medical School and the Broad Institute.
He was the lead author/analyst for the Exome Aggregation Consortium (ExAC) project that was published in Nature 2016. He went on to lead the NIH funded Broad Center for Mendelian Genomics (CMG) analysis team. As lead analyst, he oversaw the analysis strategy for all major CMG collaborations and organized monthly meetings to foster sharing of new methods and analysis amongst the rare disease community. He also coordinated the data processing and preliminary analysis of NIH Gabriella Miller Kids First (GMKF) cohorts sequenced or reprocessed at the Broad Institute.
Monkol has a strong passion for rare muscle disease research as a patient with Limb Girdle Muscular dystrophy (LGMD2G). During his time in the Broad Institute, he lead the exome/genome analysis of MYOSEQ (European cohort of >1000 LGMD patients) and SeqNMD (an international consortium of undiagnosed rare muscle diseases) which has resulted in novel disease gene discovery.
Last Updated on May 07, 2025.
Appointments
Genetics
Associate Professor on TermPrimary
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- Computational Biology and Biomedical Informatics
- Genetics
- Human Genome Sciences
- Janeway Society
- Molecular Cell Biology, Genetics and Development
- Yale Center for Genomic Health
- Yale Combined Program in the Biological and Biomedical Sciences (BBS)
- Yale-BI Biomedical Data Science Fellowship
Education & Training
- Senior Research Fellow
- Broad Institute of MIT and Harvard (2017)
- Post-doctoral Fellow
- Harvard Medical School (2016)
- PhD
- University of Sydney, Medicine (2012)
- BSc
- University of New South Wales, Physiology (2007)
- BE
- University of New South Wales, Bioinformatics (2007)
- BE
- University of New South Wales, Computer Engineering (2001)
Research
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Medical Research Interests
Genetics; Genetics, Medical; Genomics; Neuromuscular Diseases
ORCID
0000-0003-1227-6293- View Lab Website
Lek Lab
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Frequent collaborators of Monkol Lek's published research.
Publications Timeline
A big-picture view of Monkol Lek's research output by year.
Research Interests
Research topics Monkol Lek is interested in exploring.
Nicole J. Lake, PhD
Shushu Huang, MD, PhD
Hongyu Zhao, PhD
Francesc Lopez-Giraldez, PhD
Junhui Zhang, MD
Martina Brueckner, MD
38Publications
11,805Citations
Publications
2026
DNASE1L3 Deficiency With Novel Missense Variant: Enzymatic and Plasma Fragmentomic Evidence of Pathogenicity and Partial Response to JAK Blockade
Leon Tenorio A, Sugio T, Cheng J, Bonner D, Esfahani M, Kasinathan S, Hsu J, Moyer A, Pimentel Vera L, Carter J, Reuter C, Marwaha S, Balboni I, Wheeler M, Bernstein J, Alizadeh A, Gomez‐Ospina N, Tran A, Tarakad A, Balasubramanyam A, Lee B, Bacino C, Scott D, Seto E, Clark G, Dai H, Chao H, Chinn I, Orengo J, Rosenfeld J, Worley K, Burrage L, Emrick L, Potocki L, Hubshman M, Lewis R, Marom R, Lalani S, Ketkar S, Vogel T, Craigen W, Sninsky J, Blieden L, Nagamani S, Bellen H, Wangler M, Kanca O, Yamamoto S, Eng C, Ward P, Liu P, Vanderver A, Skraban C, Behrens E, Kilich G, Sullivan K, Hassey K, Rajagopalan R, Ganetzky R, Cuddapah V, Raper A, Rader D, Sirugo G, Slavotinek A, Mayhew C, Mendonca E, Guo Z, McConkie‐Rosell A, Schoch K, Mikati M, Walley N, Spillmann R, Shashi V, Beggs A, Sweetser D, Chiang D, Rao D, High F, Mochida G, Berry G, Holm I, Pallais J, Loscalzo J, Rodan L, Briere L, Walker M, Truong T, Chung W, Esteves C, Glanton E, Kohane I, LeBlanc K, Sunyaev S, Kobren S, Graham B, Conboy E, Vetrini F, Treat K, Liaqat K, Mantcheva L, Ware S, Page K, Auwaerter P, Manabe Y, Pardo‐Villamizar C, Hoover‐Fong J, Witmer P, Timp W, Robinson M, Berger Z, Wohler E, Sobreira N, Nouraee A, Prada C, Davis E, Yap K, Regan‐Fendt K, Silva M, McMullen P, Mitchell B, Lanpher B, Oglesbee D, Klee E, Pinto F, Lanza I, Darr K, Mulvihill L, Schimmenti L, Tan Q, Dasari S, Elkadri A, Bordini B, Basel D, Verbsky J, McCarrier J, Muriello M, Zimmermann M, Rebelo A, Smith C, Barbouth D, Bademci G, Gonzalez J, Latchman K, Peart L, Tekin M, Borja N, Zuchner S, Bivona S, Thorson W, Taylor H, Quarells R, Iverson A, Gelb B, Cunningham‐Rundles C, Gayle E, Jen J, Bier L, Barbosa M, Balwani M, Shadrina M, Evard R, Shuman S, Shin S, Jobanputra V, Gropman A, Pusey Swerdzewski B, Toro C, Wahl C, Novacic D, Macnamara E, Mulvihill J, Acosta M, D'Souza P, Maduro V, Afzali B, Solomon B, Tifft C, Adams D, Burke E, Rossignol F, Wood H, Fu J, Davis J, Petcharet L, Wolfe L, Delgado M, Morimoto M, Sabaii M, Malicdan M, Hanchard N, Jean‐Marie O, Introne W, Gahl W, Huang Y, Stergachis A, Miller D, Rosenthal E, Blue E, Balton E, Shelkowitz E, Allenspach E, Hisama F, Jarvik G, Mirzaa G, Glass I, Leppig K, Dipple K, Wener M, Horike‐Pyne M, Bamshad M, Byers P, Perlman S, Chanprasert S, Sybert V, Raskind W, Dargie N, Chan C, Velasquez D, Ward I, Schend J, Morgan J, Bell M, Leitheiser M, Saifeddine M, Berger P, Li R, Beagle T, Miller A, Anguiano B, Martin B, Tucker B, Reuter C, Bonner D, Kravets E, Mendez H, Tabor H, Sampson J, Hom J, Kohler J, Schymick J, Gorzynski J, Bernstein J, Smith K, Keehan L, Wiel L, Wheeler M, Halley M, Levanto M, Goddard P, Fisher P, Ungar R, Alvarez R, Emami S, Marwaha S, Montgomery S, Bachir S, Jensen T, Maurer T, Coakley T, Ashley E, Hurst A, Wilk B, Korf B, Worthey E, Callaway K, Rodriguez M, Lertwilaiwittaya P, Blackburn R, Skelton T, Mamidi T, Washington T, Crouse A, Whitlock J, Nakano‐Okuno M, Might M, Byrd W, La Spada A, Xiao C, Chao E, Vilain E, Abdenur J, Blanco K, Steenari M, Barrick R, Chang R, Attaripour S, Sandmeyer S, Mozaffar T, Huang A, Vargas A, Russell B, Fogel B, Dell'Angelica E, Carvalho G, Martínez‐Agosto J, Abi Farraj L, Butte M, Martin M, Dorrani N, Parker N, Corona R, Nelson S, Karasozen Y, Sayer D, Tousseau J, Quinlan A, Ward A, Andrews A, Welt C, Viskochil D, Baldwin E, Carey J, Alvey J, Botto L, Longo N, Moretti P, Overbury R, Butterfield R, Boyden S, Nicholas T, Velinder M, Marth G, Bayrak‐Toydemir P, Mao R, Westerfield M, Phillips J, Ezell K, Rives L, Hamid R, Krokosky A, McMinn A, Shyr C, Gamazon E, Cogan J, Perera L, Bastarache L, Koziura M, Cassini T, Paul A, Kiley D, Wegner D, McRoy E, Wambach J, Sisco K, Dickson P, Cole F, Baldridge D, Shin J, Solnica‐Krezel L, Pak S, Schedl T, Bale A, Oladele C, Hendry C, Wang E, Xu H, Zhang H, Jeffries L, Romero M, Gerstein M, Spencer‐Manzon M, Lek M, Derar N, Kaufman O, Mane S, Serrano T, Vasiliou V, Halstead W, Jiang Y. DNASE1L3 Deficiency With Novel Missense Variant: Enzymatic and Plasma Fragmentomic Evidence of Pathogenicity and Partial Response to JAK Blockade. ACR Open Rheumatology 2026, 8 PMCID: PMC12928082, DOI: 10.1002/acr2.70184.Peer-Reviewed Original ResearchAltmetricConceptsUrticarial vasculitisSystemic inflammationAnalysis of cell-free DNA fragmentsTherapeutic spectrumJAK inhibitionDNASE1L3 deficiencyBiallelic loss-of-function variantsAnti-double-stranded DNAMultiple immunosuppressive agentsPartial therapeutic benefitLoss-of-function variantsDefective clearanceHypocomplementemic urticarial vasculitisPlasma DNA analysisRecurrent abdominal painNovel missense variantsAnti-Smith antibodiesSystemic lupus erythematosusDNA fragmentation analysisEvidence of pathogenicityImmune complex depositionSensitive biomarkerCell-free DNA fragmentsWhole-exome sequencingMissense mutantsMitochondrial heteroplasmy is a risk factor for the development of chronic lymphocytic leukemia
Pasca S, Hong Y, Shi W, Puiu D, Lake N, Lek M, Guallar E, Arking D, Gondek L. Mitochondrial heteroplasmy is a risk factor for the development of chronic lymphocytic leukemia. Nature Communications 2026, 17: 2898. PMID: 41708630, PMCID: PMC13031533, DOI: 10.1038/s41467-026-69861-8.Peer-Reviewed Original ResearchAltmetricMeSH Keywords and ConceptsConceptsChronic lymphocytic leukemiaMitochondrial heteroplasmyLymphocytic leukemiaRisk of chronic lymphocytic leukemiaClonal hematopoiesis of indeterminate potentialDevelopment of chronic lymphocytic leukemiaHeteroplasmic variantsUK BiobankDeleterious variantsHeteroplasmyClonal burdenIndeterminate potentialBiological roleIndependent biomarkersMalignant transformationIndependent cohortRisk factorsBiallelic LAMP3 variants in 5 families with interstitial lung disease: Evidence of a disease-gene association
Keehan L, Ono-Minagi H, Hadhud M, Rips J, Hinds D, Fischer A, Bartlett J, McCray P, Qawasmi N, Nathan N, Louvrier C, Desroziers T, Damme M, Griese M, Wegner D, Cole F, Wambach J, Wheeler M, Burbelo P, Bonner D, Network U, Tran A, Tarakad A, Balasubramanyam A, Lee B, Bacino C, Scott D, Seto E, Clark G, Dai H, Chao H, Chinn I, Orengo J, Posey J, Rosenfeld J, Worley K, Burrage L, Emrick L, Potocki L, Hubshman M, Lewis R, Marom R, Lalani S, Ketkar S, Vogel T, Craigen W, Sninsky J, Blieden L, Nagamani S, Bellen H, Wangler M, Kanca O, Yamamoto S, Eng C, Ward P, Liu P, Vanderver A, Skraban C, Behrens E, Kilich G, Sullivan K, Hassey K, Rajagopalan R, Ganetzky R, Cuddapah V, Raper A, Rader D, Sirugo G, Jobanputra V, McConkie-Rosell A, Schoch K, Mikati M, Walley N, Spillmann R, Shashi V, Beggs A, MacRae C, Sweetser D, Rao D, Silverman E, Fieg E, High F, Berry G, Holm I, Pallais J, Stoler J, Loscalzo J, Rodan L, Cobban L, Briere L, Coggins M, Walker M, Maas R, Korrick S, Douglas J, Esteves C, Glanton E, Kohane I, LeBlanc K, Mahoney R, Sunyaev S, Kobren S, Graham B, Conboy E, Vetrini F, Treat K, Liaqat K, Mantcheva L, Ware S, Mitchell B, Lanpher B, Oglesbee D, Klee E, Pinto e Vairo F, Lanza I, Darr K, Mulvihill L, Schimmenti L, Tan Q, Dasari S, Elkadri A, Bordini B, Basel D, Verbsky J, McCarrier J, Muriello M, Zimmermann M, Rebelo A, Smith C, Barbouth D, Bademci G, Gonzalez J, Latchman K, Peart L, Tekin M, Borja N, Zuchner S, Bivona S, Thorson W, Taylor H, Quarells R, Iverson A, Gelb B, Cunningham-Rundles C, Gayle E, Jen J, Bier L, Barbosa M, Balwani M, Shadrina M, Evard R, Shuman S, Shin S, Gropman A, Swerdzewski B, Toro C, Wahl C, Novacic D, Macnamara E, Mulvihill J, Acosta M, D'Souza P, Maduro V, Afzali B, Solomon B, Tifft C, Adams D, Burke E, Rossignol F, Wood H, Fu J, Davis J, Petcharet L, Wolfe L, Delgado M, Morimoto M, Sabaii M, Malicdan M, Hanchard N, Jean-Marie O, Introne W, Gahl W, Huang Y, Stergachis A, Miller D, Rosenthal E, Blue E, Balton E, Shelkowitz E, Allenspach E, Hisama F, Jarvik G, Mirzaa G, Glass I, Leppig K, Dipple K, Wener M, Horike-Pyne M, Bamshad M, Byers P, Kumar R, Perlman S, Chanprasert S, Sybert V, Raskind W, Dargie N, Chan C, Velasq F, Ward I, Schend J, Morgan J, Bell M, Leitheiser M, Saifeddine M, Berger P, Li R, Beagle T, Miller A, Anguiano B, Martin B, Tucker B, Reuter C, Bonner D, Kravets E, Mendez H, Tabor H, Sampson J, Hom J, Kohler J, Schymick J, Gorzynski J, Bernstein J, Smith K, Keehan L, Wiel L, Wheeler M, Halley M, Levanto M, Goddard P, Fisher P, Ungar R, Alvarez R, Emami S, Marwaha S, Montgomery S, Bachir S, Jensen T, Maurer T, Coakley T, Ashley E, Al-Beshri A, Hurst A, Wilk B, Korf B, Worthey E, Callaway K, Rodriguez M, Skelton T, Mamidi T, Crouse A, Whitlock J, Nakano-Okuno M, Might M, Byrd W, La Spada A, Xiao C, Chao E, Vilain E, Abdenur J, Blanco K, Steenari M, Barrick R, Chang R, Attaripour S, Sandmeyer S, Mozaffar T, Huang A, Vargas A, Russell B, Fogel B, Dell'Angelica E, Carvalho G, Martínez-Agosto J, Farraj L, Butte M, Martin M, Dorrani N, Parker N, Corona R, Nelson S, Karasozen Y, Quinlan A, Ward A, Andrews A, Welt C, Viskochil D, Baldwin E, Carey J, Alvey J, Pace L, Botto L, Longo N, Moretti P, Overbury R, Butterfield R, Boyden S, Nicholas T, Velinder M, Marth G, Bayrak-Toydemir P, Mao R, Westerfield M, Corner B, Phillips J, Ezell K, Rives L, Hamid R, Neumann S, McMinn A, Cogan J, Cassini T, Paul A, Kiley D, Wegner D, McRoy E, Wambach J, Sisco K, Dickson P, Cole F, Baldridge D, Shin J, Solnica-Krezel L, Pak S, Schedl T, Bale A, Oladele C, Hendry C, Wang E, Xu H, Zhang H, Jeffries L, Romero M, Gerstein M, Spencer-Manzon M, Lek M, Derar N, Kaufman O, Mane S, Serrano T, Vasiliou V, Halstead W, Jiang Y, Bernstein J, Chiorini J, Breuer O, Milla C. Biallelic LAMP3 variants in 5 families with interstitial lung disease: Evidence of a disease-gene association. Genetics In Medicine 2026, 28: 102531. PMID: 41653023, DOI: 10.1016/j.gim.2026.102531.Peer-Reviewed Original ResearchAltmetricConceptsLysosome-associated membrane glycoprotein 3Interstitial lung diseaseChildhood interstitial lung diseaseLung diseaseIn vitro effectsInterstitial lung disease phenotypeLamellar bodiesBiallelic variantsGenetic causeAlveolar epithelial type II cellsNeonatal respiratory distressEpithelial type II cellsGround-glass opacitiesAsymptomatic in adulthoodLung disease phenotypesLung epithelial cellsIn vitro studiesType II cellsLung biopsyBAL analysisSurfactant dysfunctionChart reviewGlass opacitiesLung fibrosisRespiratory distressP656: Rare genetic mechanisms in DYM-related Dyggve–Melchior–Clausen disease
Jacob, Bhat D, Gopika K, K M, Lek M, Patil S. P656: Rare genetic mechanisms in DYM-related Dyggve–Melchior–Clausen disease. Genetics In Medicine Open 2026, 4: 104146. DOI: 10.1016/j.gimo.2026.104146.Peer-Reviewed Original Research
2025
Phenotypic Variability and Paternal Inheritance of a CHD8 Variant Causing Intellectual Developmental Disorder With Autism and Macrocephaly Confirmed by Epigenetic and Structural Analyses
Furuta Y, Ezell K, Hamid R, Cogan J, Cassini T, Rives L, McMinn A, Shah S, Peltier A, Layfield S, Fletcher R, Tedder M, Louie R, Lee J, Kerkhof J, Rzasa J, Sadikovic B, Al Mamun A, Sheehan J, Moth C, Meiler J, Vawter‐Lee M, Mendoza‐Sengco P, Holzen J, Pruthi S, Phillips J, Tinker R, Quinlan A, Elkadri A, Vanderver A, Rebelo A, Beggs A, La Spada A, Huang A, Paul A, Miller A, Al‐Beshri A, Ward A, Bale A, McConkie‐Rosell A, Tran A, Gropman A, Vargas A, Crouse A, Stergachis A, Hurst A, Raper A, Tarakad A, Andrews A, McMinn A, Balasubramanyam A, Swerdzewski B, Anguiano B, Afzali B, Solomon B, Martin B, Russell B, Wilk B, Mitchell B, Lanpher B, Lee B, Fogel B, Bordini B, Graham B, Corner B, Tucker B, Korf B, MacRae C, Toro C, Skraban C, Bacino C, Oladele C, Hendry C, Smith C, Esteves C, Xiao C, Reuter C, Eng C, Chan C, Wahl C, Welt C, Tifft C, Kiley D, Rader D, Wegner D, Miller D, Scott D, Viskochil D, Sweetser D, Adams D, Barbouth D, Rao D, Oglesbee D, Bonner D, Basel D, Novacic D, Baldridge D, Behrens E, Silverman E, Seto E, Kravets E, Rosenthal E, Worthey E, Burke E, Blue E, Chao E, Fieg E, Macnamara E, Balton E, Glanton E, Shelkowitz E, Wang E, Allenspach E, Klee E, Vilain E, Conboy E, Baldwin E, McRoy E, Dell’Angelica E, Ashley E, Cole F, Pinto e Vairo F, High F, Vetrini F, Rossignol F, Bustos F, Hisama F, Marth G, Jarvik G, Clark G, Carvalho G, Berry G, Mirzaa G, Sirugo G, Kilich G, Bademci G, Mendez H, Wood H, Taylor H, Tabor H, Dai H, Chao H, Xu H, Bellen H, Zhang H, Glass I, Lanza I, Holm I, Kohane I, Ward I, Chinn I, Pallais J, Sampson J, Orengo J, Verbsky J, Sninsky J, Hom J, Schend J, Kohler J, Posey J, Morgan J, Schymick J, Wambach J, Douglas J, Fu J, Rosenfeld J, Shin J, Stoler J, Gonzalez J, Phillips J, Carey J, Gorzynski J, Mulvihill J, Davis J, Bernstein J, Whitlock J, Abdenur J, Loscalzo J, Cogan J, Martínez‐Agosto J, McCarrier J, Alvey J, Darr K, Callaway K, Leppig K, Sullivan K, Sisco K, Singh K, Dipple K, Treat K, Hassey K, Schoch K, Smith K, Liaqat K, Worley K, Ezell K, LeBlanc K, Latchman K, Rodan L, Keehan L, Pace L, Cobban L, Blieden L, Briere L, Jeffries L, Wiel L, Farraj L, Petcharet L, Peart L, Mantcheva L, Solnica‐Krezel L, Burrage L, Mulvihill L, Schimmenti L, Emrick L, Botto L, Potocki L, Rives L, Wolfe L, Steenari M, Butte M, Delgado M, Romero M, Acosta M, Morimoto M, Nakano‐Okuno M, Gerstein M, Wener M, Sabaii M, Horike‐Pyne M, Martin M, Rodriguez M, Velinder M, Coggins M, Might M, Wheeler M, Malicdan M, Bell M, Halley M, Walker M, Levanto M, Bamshad M, Wangler M, Muriello M, Zimmermann M, Spencer‐Manzon M, Leitheiser M, Mikati M, Saifeddine M, Hubshman M, Lek M, Westerfield M, Tekin M, Derar N, Dorrani N, Parker N, Hanchard N, Borja N, Longo N, Walley N, Dargie N, Kaufman O, Kanca O, Jean‐Marie O, Goddard P, Moretti P, Ward P, Dickson P, Berger P, Fisher P, Liu P, Byers P, Bayrak‐Toydemir P, D’Souza P, Tan Q, Ungar R, Li R, Mahoney R, Rajagopalan R, Alvarez R, Spillmann R, Ganetzky R, Overbury R, Barrick R, Lewis R, Maas R, Hamid R, Mao R, Marom R, Corona R, Kumar R, Butterfield R, Attaripour S, Nagamani S, Emami S, Lalani S, Neumann S, Perlman S, Ketkar S, Sunyaev S, Kobren S, Yamamoto S, Mane S, Marwaha S, Chanprasert S, Nelson S, Zuchner S, Bivona S, Ware S, Montgomery S, Pak S, Boyden S, Bachir S, Dasari S, Korrick S, Sandmeyer S, Mozaffar T, Skelton T, Jensen T, Mamidi T, Beagle T, Maurer T, Serrano T, Coakley T, Cassini T, Nicholas T, Schedl T, Vogel T, Jobanputra V, Maduro V, Shashi V, Vasiliou V, Sybert V, Cuddapah V, Introne W, Raskind W, Thorson W, Gahl W, Byrd W, Craigen W, Halstead W, Huang Y, Karasozen Y, Jiang Y. Phenotypic Variability and Paternal Inheritance of a CHD8 Variant Causing Intellectual Developmental Disorder With Autism and Macrocephaly Confirmed by Epigenetic and Structural Analyses. Molecular Genetics & Genomic Medicine 2025, 13: e70165. PMID: 41407309, PMCID: PMC12711360, DOI: 10.1002/mgg3.70165.Peer-Reviewed Original ResearchAltmetricMeSH Keywords and ConceptsConceptsUndiagnosed Diseases NetworkStructural biology analysesGenome sequenceVariant pathogenicityDNA methylation analysisDe novo pathogenic variantAutosomal dominant neurodevelopmental disorderBiological analysisMethylation patternsIntellectual developmental disorderDominant neurodevelopmental disorderProtein destabilizationPathogenic variantsPaternal inheritanceCHD8Phenotypic variabilityMethylation analysisParental inheritanceDisease networkPathogensGenomeVUSFemale probandsVariantsDevelopmental disordersODAD4-Related Primary Ciliary Dyskinesia: Report of Five Cases and a Founder Variant in Quebec
Bourassa M, Sillon G, Ding S, Chioccioli M, Lek M, Ma K, Mejia-Garcia A, Gravel S, Vinh D, Knowles M, Leigh M, Davis S, Ferkol T, Olivier K, Schecterman E, Yin W, Sears P, Gentzsch M, Boyles S, Bennett W, Zeman K, Ostrowski L, Zariwala M, Shapiro A. ODAD4-Related Primary Ciliary Dyskinesia: Report of Five Cases and a Founder Variant in Quebec. Cells 2025, 14: 1460. PMID: 41002425, PMCID: PMC12468610, DOI: 10.3390/cells14181460.Peer-Reviewed Original ResearchAltmetricMeSH Keywords and ConceptsConceptsPrimary ciliary dyskinesiaIn-frame skippingCiliary dyskinesiaChronic oto-sino-pulmonary diseaseOto-sino-pulmonary diseaseNasal nitric oxide levelsMild formOuter dynein arm defectsDevelopment of bronchiectasisDynein arm defectsSkipping of exon 2Nitric oxide levelsReverse transcription polymerase chain reactionPulmonary phenotypePulmonary function valuesTranscription polymerase chain reactionRadiographic pneumoniaPolymerase chain reactionFounder variantPathogenic variantsAbnormal splicingMucociliary clearanceDiagnostic evaluationRespiratory symptomsExon 2Reversible compromise of physiological resilience by accumulation of heteroplasmic mtDNA mutations
Huang H, Wang Y, Zsengeller Z, Gorham J, Vemireddy V, Clark A, Pan H, Dreyfuss J, Jotwani V, Shlipak M, Sarnak M, Parikh C, Thiessen-Philbrook H, Katz R, Waikar S, Lake N, Lek M, Shi W, Puiu D, Hong Y, Seidman J, Arking D, Parikh S. Reversible compromise of physiological resilience by accumulation of heteroplasmic mtDNA mutations. Science 2025, 390: 164-172. PMID: 40906782, PMCID: PMC12892176, DOI: 10.1126/science.adk7978.Peer-Reviewed Original ResearchCitationsAltmetricConceptsHeteroplasmic mtDNA mutationsMtDNA mutationsAdenylate kinase 4Purine biosynthetic enzymesMitochondrial DNA mutationsMetabolically active cellsPurine biosynthesisBiosynthetic enzymesDNA mutationsNucleotide metabolismATP generationMutationsKinase 4NucleotidePhysiological resilienceActive cellsUK Biobank participantsMtDNABiosynthesisCumulative effectBiobank participantsAdenylateMutational burdenEnzymeATPProtocol to implement saturation mutagenesis-reinforced functional assays to resolve small-sized variants in disease-related genes
Gauthier L, Wang Z, Ng K, Huang S, Mao Y, Lek M, Ma K. Protocol to implement saturation mutagenesis-reinforced functional assays to resolve small-sized variants in disease-related genes. STAR Protocols 2025, 6: 103909. PMID: 40540392, PMCID: PMC12221425, DOI: 10.1016/j.xpro.2025.103909.Peer-Reviewed Original ResearchAltmetricConceptsDisease-related genesDisease-causing genetic variantsFluorescence-based cell sortingNext-generation sequencingFunctional assaysDisease genesAllelic seriesSaturation mutagenesisGenetic variantsGenesFunctional impactCell sortingHigh-throughputVariantsDisease fieldAssayMutagenesisSequenceCellsNucleofectionSortingPrecision multiplexed base editing in human cells using Cas12a-derived base editors
Schweitzer A, Adams E, Nguyen M, Lek M, Isaacs F. Precision multiplexed base editing in human cells using Cas12a-derived base editors. Nature Communications 2025, 16: 5061. PMID: 40449999, PMCID: PMC12126522, DOI: 10.1038/s41467-025-59653-x.Peer-Reviewed Original ResearchCitationsAltmetricMeSH Keywords and ConceptsConceptsMultiplex base editingBase editingBase editorsBase editor variantsMammalian genome engineeringBase editing technologyGenome engineering technologiesDNA double strand breaksBase editing systemMammalian genomesDouble strand breaksMultiple lociPolygenic phenotypesHuman cell linesHuman genomeGenome engineeringTarget nucleotideEditing outcomesMutation rateMultiplex editingMultiple gRNAsHuman cellsExpression cassetteEditing technologyGenomeUntargeted proteomics enables ultra-rapid variant prioritisation in mitochondrial and other rare diseases
Hock D, Caruana N, Semcesen L, Lake N, Formosa L, Amarasekera S, Stait T, Tregoning S, Frajman L, Bournazos A, Robinson D, Ball M, Reljic B, Ryder B, Wallis M, Vasudevan A, Beck C, Peters H, Lee J, Tan N, Freckmann M, Karlaftis V, Attard C, Monagle P, Samarasinghe A, Brown R, Bi W, Lek M, McFarland R, Taylor R, Ryan M, Cooper S, Stark Z, Christodoulou J, Compton A, Thorburn D, Stroud D. Untargeted proteomics enables ultra-rapid variant prioritisation in mitochondrial and other rare diseases. Genome Medicine 2025, 17: 58. PMID: 40400026, PMCID: PMC12096736, DOI: 10.1186/s13073-025-01467-z.Peer-Reviewed Original ResearchCitationsAltmetricMeSH Keywords and ConceptsConceptsMitochondrial diseaseProteomic dataGenome sequenceDisease genesPathogenicity of novel variantsFunctional validationMitochondrial disease genesMendelian disease genesValidation of genetic variantsGenetic diagnosisInterpretation of variantsPeripheral blood mononuclear cellsVariant prioritisationMitochondrial genesApplication of proteomicsVariant pathogenicityProteomic testBioinformatics toolsNovel variantsGenetic variantsRNA sequencingPathogenic variantsProteomics pipelineProteomicsGenomic testing
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Pediatric Genomics Discovery Program (PGDP)
IRB ID1411014977RoleSub InvestigatorPrimary Completion Date12/31/2023Recruiting ParticipantsGenderBoth
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Honors
honor Development Grant
01/01/2016National AwardMuscular Dystrophy AssociationDetailsUnited Stateshonor CJ Martin Fellowship
06/01/2013International AwardAustralian National Health and Medical Research Council (NHMRC)DetailsAustraliahonor Sir Keith Murdoch Fellowship
08/01/2012International AwardAustralian American AssociationDetailsAustraliahonor Australian Post-graduate Award
03/01/2009International AwardUniversity of SydneyDetailsAustraliahonor University Medal
03/01/2008International AwardUniversity of New South WalesDetailsAustralia
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News
- June 09, 2025Source: Yale News
Yale Genome Engineers Expand the Reach and Precision of Human Gene Editing
- December 02, 2024
This Faster, Low-tech Test Identifies Rare Disease-causing Genetic Mutations
- September 10, 2024
NIH Recognizes Yale’s Expertise in the Genetics of Rare Diseases
- June 07, 2024
Polycystic Kidney Disease Treatment: Gene Target Identified at Yale
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