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Santhosh Girirajan

Interim Department Head and Professor of Genomics in the Department of Biochemistry and Molecular Biology
Santhosh Girirajan.

Research Interest

Genetics of neurodevelopmental disorders


Research Summary

'All happy families are alike; each unhappy family is unhappy in its own way.' The latter part of this quote from Tolstoy forms the central theme of my research – why do genetic disorders affect each family differently? Until recently, genetics research focused on identifying individual genes or variants as causal for human diseases, conforming to Mendelian paradigms. However, this notion is overly simplistic, and my research has contributed to unraveling the complexity of genetic disorders. Previously, I was involved in identifying >20 rare (<0.1% prevalence) deletions and duplications that collectively account for >25% of individuals with neurodevelopmental disorders, such as autism and intellectual disability. These variants encompass multiple genes, many with putative roles in brain development. we found that the same rare variant (such as a deletion on chromosome 16p12.1) can lead to varying clinical outcomes even among members of the same family. Therefore, we proposed a model where a rare variant sensitizes the genome for a range of disease outcomes but leads to distinct trajectories in concert with other variants in the genome or epigenetic or environmental factors. As I anticipated that further research into this model would transcend multiple fields, I invested efforts to build resources in genetics, neuroscience, molecular biology, bioinformatics, and systems biology and develop a positive learning environment in my lab. My mentorship philosophy of supporting trainees to work independently and develop their own experimental strategies to address their hypotheses has resulted in training the next generation of experts and contributed to my lab’s success. 

My research has contributed to identifying genetic combinations and biological mechanisms causing disease variability. Recruiting families with rare mutations is challenging as large numbers are needed to achieve statistical power. Therefore, I spent considerable efforts building a cohort of families with 16p12.1 deletion and other rare variants by organizing parent support groups to promote awareness and foster partnerships with caregivers, forming an international network of >25 clinical sites for continuing recruitment efforts, and establishing collaborations with an interdisciplinary team of clinicians for quantitative assessment of patients across cognitive, developmental, and psychiatric domains. Funded by the National Institutes of Health (NIH) and foundations such as the Simons Foundation and March of Dimes, we recruited hundreds of families with 16p12.1 deletion for genome sequencing and detailed clinical evaluation, representing one of the largest collections for any such variant to date. Given the enormity of data generated, we have built computational resources and developed bioinformatic pipelines and novel algorithms for identifying variants and connecting genetic data to clinical outcomes. The culture of encouraging out-of-the-box thinking in my lab allowed us to generate innovative ways to solve complex problems. For example, we developed a method to detect combinations of mutated genes conferring risk for autism that is derived from market basket analysis typically used in marketing (e.g., customers purchasing bread are more likely to purchase milk and eggs). Using these computational frameworks, we found that 16p12.1 deletion carriers have specific genetic signatures conferring risk for distinct phenotypes. For example, more rare variants increased risk for ID in affected children, while expanded repeats led to nervous system defects. The severity of disease also correlated with family history of neuropsychiatric disease. We further found that parents of affected children were more likely to have similar psychiatric phenotypes (a phenomenon called “assortative mating”). For example, parents with depression or anxiety who carried the 16p12.1 deletion were more likely to have partners with depression or anxiety due to other variants. This finding provides a model for how different mutations from parents with similar phenotypes come together to cause more severe disease in subsequent generations. We are expanding our study to gather 1,000 families with 16p12.1 deletion and other CNVs ascertained through direct recruitment, electronic health records, and general population cohorts. 

While human genetic studies can direct counseling and early childhood intervention, functional studies in model systems would help identify disease mechanisms and potential molecular targets for therapy. However, there are several challenges with doing functional work on my genetic discoveries. Generating mutations of individual and combinations of genes and testing their effects on mammalian nervous system models would be time consuming, expensive, and daunting. Luckily, a chance reading of a biography of pioneering fruit fly geneticist Seymour Benzer (Time, Love, Memory by Jonathan Weiner) inspired me to work with fruit flies. Drosophila melanogaster serves as an excellent system for my studies, as flies reproduce quickly and have conserved developmental processes, synaptic mechanisms, and neural structure and signaling with humans. Therefore, I spent considerable efforts to establish a robust Drosophila research program, obtained NIH support, and formed collaborations with experts studying Xenopus laevis (frog) and zebrafish models to complement our fly work. The strategy of using flies worked. We published ten papers recapitulating results from our human studies and identifying specific neuronal mechanisms of pathogenic deletions that are modulated by genetic interactions. Notably, our findings were later replicated in other model organism studies. I owe my success to the environment at Penn State, talented postdocs, graduate students, and 60+ undergraduate students mostly recruited from my genomics class, who tested over 12,000 fly lines and 1000 genetic interactions in the nervous system. To expand our findings from fly, frog, and fish models, we are currently conducting studies in mice as well as differentiating patient-derived induced pluripotent stem cells to “brain-in-a-dish” systems to identify mammal and human-specific mechanisms of disease. My future research will use integrative strategies to study hundreds of genes and genetic interactions to dissect the complexity of genetic disease, untangle molecular subtypes, and provide an understanding of disease pathogenesis. Such knowledge can be used to define the molecular basis of disease and to identify therapeutic targets for these disorders. I envision that my research will further transition towards neuroscience, developmental biology, and biochemistry as we continue to uncover the deeper complexity of gene function in neurodevelopment.

Selected Publications

(aGraduate student, bUndergraduate student, cPostdoctoral fellow, #Corresponding author)

  • Das Ma, Hossain A, Banerjee D, Praul CA, Girirajan S#. Challenges and considerations for reproducibility of STARR-seq assays. Genome Research 2023 Apr;33(4):479-495. doi: 10.1101/gr.277204.122. Epub 2023 May 2. PMID: 37130797

  • Mhatre SD*, Iyer J*, Peteriet J, Dolling-Boreham RM, Tyryshkina Aa, Paul A, Gilbert R, Jensen M, Woolsey RJ, Anand S, Sowa MB, Quilici DR, Costes SV, Girirajan S, and Bhattacharya S. Artificial Gravity Delays Space-induced Neurological Deficits 1 in Drosophila melanogaster. Cell Reports. Sep 6;40(10):111279. doi: 10.1016/j.celrep.2022.111279. PMID: 36070701.
  • Pounraja VKa and Girirajan S#. Oligogenic combinations of rare variants influence specific phenotypes in complex disorders. Genome Research, 2022. Mar 17:gr.276348.121. doi: 10.1101/gr.276348.121. PMID: 35301265.
  • Jensen Ma, Tyryshkina Aa, Pizzo La, Smolen Ca, Das Ma, Huber Eb, Krishnan A, Girirajan S#. Combinatorial patterns of gene expression changes contribute to variable expressivity of a complex disorder. Genome Medicine, 2021. Oct 18;13(1):163. doi: 10.1186/s13073-021-00982-z. PMID: 34657631.

  • Pizzo La, Lasser M*, Yusuff Tc, Jensen Ma, Ingraham Pa, Huber Ea, Singh MDc, Monahan C, Iyer Jc, Desai Ib, Karthikeyan Sb, Gould DJb, Yennawar Sb, Weiner AT, Pounraja VKa, Krishnan A, Rolls MM, Lowery LA, Girirajan S#. Functional assessment of the "two-hit" model for neurodevelopmental defects in Drosophila and X. laevis. PLOS Genetics. 2021 Apr 5;17(4):e1009112. PMID: 33819264.

  • Yusuff Tc, Jensen Ma, Yennawar Sb, Pizzo La, Karthikeyan Sb, Gould DJb, Sarker Ab, Matsui Y, Lai Z-C, Girirajan S#. Drosophila models of pathogenic copy-number variant genes show global and non-neuronal defects during development. PLOS Genetics, 2020. PMID: 32579612    

  • Jensen Mc, Smolen Ca, Girirajan S#. Gene discoveries in autism are biased towards comorbidity with intellectual disability. Journal of Medical Genetics, 2020 March 9. PMID: 31252248
  • Singh MDc, Jensen Ma, Lasser M, Huber Eb, Yusuff Tc, Pizzo La, Lifshutz Bb, Desai Ib, Kubina Ab, Yennawar Sb, Kim S, Iyer Jc, Rincon-Limas D, Lowery LA, Girirajan S#. NCBP2 modulates neurodevelopmental defects of the 3q29 deletion in Drosophila and X. laevis models. PLOS Genetics, 2020 February 13. PMID: 32053595
  • Pounraja VKa, Jayakar Gb, Jensen Ma, Kelkar Nb, Girirajan S#. A machine-learning approach for accurate detection of copy-number variants from exome sequencing. Genome Research. 2019 June 6. PMID: 31171634.
  • Pizzo La, Jensen Ma, Polyak Ab, Rosenfeld JA, Mannik K, Krishnan A, McCready E, Pichon O, Le Caignec C, Van Dijck A, Pope K, Voorhoeve E, Yoon Jb, Stankiewicz P, Cheung SW, Pazuchanics Db, Huber Eb, Kumar Va, Kember RL, Mari F, Curró A, Castiglia L, Galesi O, Avola E, Mattina T, Fichera M, Mandarà L, Vincent M, Nizon M, Mercier S, Bénéteau C, Blesson S, Martin-Coignard D, Mosca-Boidron AL, Caberg JH, Bucan M, Zeesman S, Nowaczyk MJM, Lefebvre M, Faivre L, Callier P, Skinner C, Keren B, Perrine C28, Prontera P, Marle N, Renieri A, Reymond A, Kooy RF, Isidor B, Schwartz C, Romano C, Sistermans E, Amor DJ, Andrieux J, Girirajan S#. Rare variants in the genetic background modulate cognitive and developmental phenotypes in individuals carrying disease-associated variants. Genetics in Medicine, 2018 Sep. 7. PMID: 30190612.
  • Iyer Jc, Singh MDc, Jensen Ma, Patel Pb, Pizzo La, Huber Eb, Koerselman H, Weiner A, Lepanto P, Vadodaria Kb, Kubina Ab, Wang Qa, Talbert Ab, Yennawar Sb, Badano J, Manak JR, Rolls MM, Krishnan A, Girirajan S#. Pervasive epistasis in cell proliferation pathways modulates neurodevelopmental defects of the autism-associated 16p11.2 deletion. Nature Communications, 2018 Jun 29;9(1):2548. PMID: 29959322.
  • Wang Qa, Shashikant CS, Jensen Ma, Altman NS, Girirajan S#. Novel metrics to measure coverage in whole exome sequencing datasets reveal local and global non-uniformity. Scientific Reports. 2017 Apr 13;7(1):885. PMID: 28408746. #Corresponding author.  

  • Iyer Jc, Wang Qa, Le Ta, Pizzo Pa, Grönke, Ambegaokar SS, Imai Y, Srivastava A, Llamusí B, Mardon G, Artero G, Jackson GR, Isaacs AM, Partridge L, Lu B, Kumar JP, Girirajan S#. Quantitative assessment of eye phenotypes for functional genetic studies using Drosophila melanogaster. G3: Genes Genomes Genetics. 2016 May 3;6(5):1427-37. PMID: 26994292.

  • Polyak Ab, Rosenfeld JA, Girirajan S#. An assessment of sex bias in neurodevelopmental disorders. Genome Medicine, 2015 Aug 27;7(1):94. PMID: 26307204.

  • Polyak Ab, Kubina R, Girirajan S#. Comorbidity of intellectual disability confounds ascertainment of autism: Implications for genetic diagnosis. American Journal of Medical Genetics Part B, Neuropsychiatric Genetics, 2015 Oct;168(7):600-8. PMID: 26198689.  

  • Girirajan S#, Johnson RL, Tassone F, Balciuniene J, Katiyar N, Fox K, Baker C, Srikanth A, Yeoh K-H, Khoo SJ, Nauth TB, Hansen R, Ritchie MD, Hertz-Picciotto I, Eichler EE, Pessah IN, Selleck SB#. Global increases in both common and rare copy number load associated with autism. Human Molecular Genetics, 2013, Jul 15;22(14):2870-2880. PubMed PMID: 23535821.

  • Girirajan S*, Dennis MY*, Baker C, Malig M, Coe BP, Campbell CD, Mark K, Vu TH, Alkan C, Cheng Z, Biesecker LG, Bernier R, and Eichler EE. Refinement and discovery of new hotspots of copy number variation associated with autism spectrum disorder. American Journal of Human Genetics, 2013, Feb 7;92(2):221-237. PubMed PMID: 3375656. *Contributed equally.

  • Girirajan S*, Rosenfeld JA*, Coe BP, Parikh S, Friedman N, Goldstein A, Filipink RA, McConnell JS, Angle B, Meschino WS, Nezarati M, Asamoah A, Jackson KE, Gowans GC, Martin JA, Penney LS, Martin DM, Raskin S, Leppig K, Thiese H, Smith R, Aberg E, Niyazov DM, Escobar LF, El-Khechen D, Johnson KD, Lebel RR, Siefkas K, Ball S, Shur N, McGuire M, Brasington CK, Spence JE, Martin LS, Clericuzio C, Ballif BC, Shaffer LG, Eichler EE. Phenotypic heterogeneity of genomic disorders and rare copy number variants.  New England Journal of Medicine, 2012, Oct 4;367(14):1321-1331. PubMed PMID: 22970919. *Contributed equally.

  • O’Roak BJ, Vives L, Girirajan S, Karakoc E, Krumm N, Coe BP, Levy R, Ko A, Lee C, Smith JD, Turner EH, Stanaway IB, Vernot B, Malig M, Baker C, Reilly B, Akey JM, Borenstein E, Rieder MJ, Nickerson DA, Bernier R, Shendure J, and Eichler EE. Exome sequencing in sporadic autism reveals a highly interconnected protein network and extreme locus heterogeneity. Nature, 2012, Apr 4;485(7397):246-250. PubMed PMID: 22495309.

  • Vu T, Coccaro E, Eichler EE, Girirajan S#. Genomic architecture of aggression: Rare CNVs in intermittent explosive disorder. American Journal of Medical Genetics Part B, Neuropsychiatric Genetics, 2011, Dec;156B(7):808-816. PubMed PMID: 21812102.

  • Girirajan S, Brkanac Z, Coe BP, Baker C, Vives L, Vu TH, Shafer N, Bernier R, Ferrero GB, Silengo M, Warren ST, Moreno CS, Fichera M, Romano C, Raskind WH, Eichler EE. Relative burden of large CNVs on a range of neurodevelopmental phenotypes. PLOS Genetics, 2011, Nov;7(11);1-17. PubMed PMID: 22102821.

  • Cooper GM*, Coe BP*, Girirajan S*, Rosenfeld JA, Vu TH, Baker C, Williams C, Stalker H, Hamid R, Hannig V, Abdel-Hamid H, Bader P, McCracken E, Niyazov D, Leppig K, Thiese H, Hummel M, Alexander N, Gorski J, Kussmann J, Shashi V, Johnson K, Rehder C, Ballif BC, Shaffer LG, Eichler EE. A copy number variation morbidity map of developmental delay. Nature Genetics, 2011, Aug 14;43(9):838-846. PubMed PMID: 21841781. *Contributed equally.

  • Girirajan S*, Rosenfeld JA*, Cooper GM, Antonacci F, Siswara P, Itsara A, Vives L, Walsh T, McCarthy SE, Baker C, Mefford HC, Kidd JM, Browning SR, Browning BL, Dickel DE, Levy DL, Ballif BC, Platky K, Farber DM, Gowans GC, Wetherbee JJ, Asamoah A, Weaver DD, Mark PR, Dickerson J, Garg BP, Ellingwood SA, Smith R, Banks VC, Smith W, McDonald MT, Hoo JJ, French BN, Hudson C, Johnson JP, Ozmore JR, Moeschler JB, Surti U, Escobar LF, El-Khechen D, Gorski JL, Kussmann J, Salbert B, Lacassie Y, Biser A, McDonald-McGinn DM, Zackai EH, Deardorff MA, Shaikh TH, Haan E, Friend KL, Fichera M, Romano C, Gécz J, DeLisi LE, Sebat J, King M-C, Shaffer LG, Eichler EE. A recurrent 16p12.1 microdeletion supports a two-hit model for severe developmental delay. Nature Genetics, 2010, Mar;42(3):203-209. PubMed PMID: 20154674. *Contributed equally.

  • Girirajan S, Elsea, SH. Distorted Mendelian transmission as a function of genetic background in Rai1-haploinsufficient mice. European Journal of Medical Genetics, 2009, Jul-Aug;52(4): 224-228. PubMed PMID: 19116176.

  • Girirajan S, Truong HT, Blanchard CL, Elsea SH. A functional network module for Smith-Magenis syndrome. Clinical Genetics, 2009, Jul;75(4):364-374. PubMed PMID: 19236431.

  • Girirajan S, Elsea SH. Abnormal maternal behavior, altered sociability, and impaired serotonin metabolism in Rai1-transgenic mice. Mammalian Genome, 2009, Apr 20(4):247-255. PubMed PMID: 19417538.

  • Girirajan S, Chen L, Graves T, Marques-Bonet T, Ventura M, Fronick C, Fulton L, Rocchi M, Fulton R, Wilson RK, Mardis ER, Eichler EE. Sequencing human-gibbon breakpoints of synteny reveals mosaic new insertions at rearrangement sites. Genome Research, 2009, Feb;19(2):178-190. PubMed PMID: 19029537.

  • Girirajan S, Patel N, Slager RE, Tokarz ME, Bucan M, Wiley JL, Elsea SH. How much is too much? Phenotypic consequences of Rai1 overexpression in mice. European Journal of Human Genetics, 2008, Aug;16(8):941-954. PubMed PMID: 18285828.

  • Girirajan S, Hauck PM, Williams SR, Vlangos CN, Szomju BB, Solaymani-Kohal S, Mosier PD, McCoy KL, White KL, Elsea SH. Tom1l2 hypomorphic mice exhibit increased incidence of infections and tumors and abnormal immunological response. Mammalian Genome, 2008, Apr;19(4):246-262. PubMed PMID: 18343975.

  • Girirajan S, Williams SR, Garbern JY, Hatchwell E, Elsea SH. 17p11.2 triplication and del(17)(q11.2q12) in a severely affected child with dup(17)(p11.2p12) syndrome. Clinical Genetics, 2007, Jul;72(1):47-58. PubMed PMID: 17594399.

  • Girirajan S, Mendoza-Londono R, Vlangos CN, Bunyan DJ, Hatchwell E, Elsea SH. Smith-Magenis syndrome and Moyamoya disease in a patient with del(17)(p11.2p13.1). American Journal of Medical Genetics Part A, 2007, May 1;143A(9):999-1008. PubMed PMID: 17431895.

  • Girirajan S, Vlangos CN, Szomju B, Edelman E, Trevors CD, Dupuis L, Nezarati M, Bunyan DJ, Elsea SH.  Genotype-phenotype correlation in Smith-Magenis syndrome: Evidence that multiple genes in 17p11.2 contribute to the clinical spectrum. Genetics in Medicine, 2006, Jul 8(7):417-427. PubMed PMID: 16845274.

  • Girirajan S, Elsas II LJ, Devriendt KH, Elsea SH. RAI1 variations in Smith-Magenis syndrome patients without 17p11.2 deletions. Journal of Medical Genetics, 2005, Nov;42(11):820-828. PubMed PMID: 15788730.


Selected Reviews, Previews, and Book Chapters

  • Banerjeea, Girirajan S#. Pathogenic variants and ascertainment: Neuropsychiatric disease risk in a health system cohort. American Journal of Psychiatry. 2023.
  • Smolen Ca, Girirajan S#. The gene dosage makes the disease. Cell, 2022. Aug 4;185(16):2850-2852. doi: 10.1016/j.cell.2022.07.005.

  • Das Ma, Girirajan S#. Genetic subtypes, allelic effects, and convergent neurodevelopmental mechanisms. Genome Medicine, 2021 Jun 7;13(1):99. doi: 10.1186/s13073-021-00913-y.

  • Yusuff TcKellaris G, Girirajan S#, Katsanis N#. Dissecting the complexity of CNV pathogenicity: insights from Drosophila and zebrafish models. Current Opinion in Genetics and Medicine, 2021, March. PMID: 33812298.

  • Jensen Ma, Girirajan S#. An interaction-based model for neuropsychiatric features of copy-number variants. PLOS Genetics, 2019 Jan. 17;15(1):e1007879. PMID: 30653500.

  • Pounraja VKa, Girirajan S#. Molecular basis for phenotypic similarity of genetic disorders. Genome Medicine, 11(1)24, 2019. PMID: 31014384.

  • Girirajan S#, Pizzo La, Moeschler J, Rosenfeld JA. 16p12.2 deletion, In: GeneReviews, Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. 2015 Feb 26 [updated 2018 Sep 13]. Pubmed PMID: 25719193.

  • Jensen MaGirirajan S#. Mapping a shared genetic basis for neurodevelopmental disorders. Genome Medicine, 2017 Dec 14;9(1):109. PMID: 29241461. #Corresponding author.

  • Girirajan S#. Missing heritability and where to find it. Genome Biology, 2017 May 11;18(1):89.

  • Pizzo La, Andrieux J, Amor DJ, Girirajan S#. Clinical utility gene card for: 16p12.2 microdeletion. European Journal of Human Genetics, 2016, Nov 16. PMID: 27848943.

  • Iyer Jc, Girirajan S#. Gene discovery and functional assessment of rare copy-number variants in neurodevelopmental disorders. Briefings in Functional Genomics, 2015 Sep;14(5):315-28. Pubmed PMID: 25971441.

  • Ghosh D, Girirajan S. ‘Statistical considerations in the analysis of rare variants’ in Statistical analysis of next generation sequencing data, Ed. Datta S, Nettleton D, Springer, Heidelberg, 2014.

  • Girirajan S#. Genomic disorders: complexity at multiple levels. Genome Medicine, 2013, May 29;5(5)43.

  • Queitsch C, Carlson KS, and Girirajan S. Lessons from model organisms: Phenotypic robustness and missing heritability in complex disease. PLOS Genetics, 2012, Nov;8(11): e1003041. PubMed PMID: 23166511.

  • Girirajan S, Eichler EE. De novo CNVs in bipolar disorder: Recurrent themes or new directions? Neuron, 2011, Dec 22;72(6):885-887. PubMed PMID: 22196322.

  • Girirajan S, Campbell CD, Eichler EE. Human copy number variation and complex genetic disease.  Annual Reviews of Genetics, 2011, Feb 7;92(2):221-237. PubMed PMID: 21854229.

  • Girirajan S, Eichler EE. Phenotypic variability and genetic susceptibility to genomic disorders. Human Molecular Genetics, 2010, Oct 15;19(R2):R176-187. PubMed PMID: 20807775.

  • Marques-Bonet T, Girirajan S, Eichler EE. The origins and impact of primate segmental duplications. Trends in Genetics, 2010, Oct;25:443-454. PubMed PMID: 19796838.

  • Girirajan S#. Parental-age effects in Down syndrome. Journal of Genetics, 2009, Apr;88(1):1-7. PubMed PMID: 19417538.

  • Elsea SH, Girirajan S. Smith-Magenis syndrome. European Journal of Human Genetics, 2008, Apr;16(4):412-421. PubMed PMID: 18231123.

  • Girirajan S, Elsea SH. Brachydactyly A1: New relatives for old families? Journal of Genetics, 2005, Aug;84(2):95-98. PubMed PMID: 16131709.