Network


Latest external collaboration on country level. Dive into details by clicking on the dots.

Hotspot


Dive into the research topics where Santhosh Girirajan is active.

Publication


Featured researches published by Santhosh Girirajan.


Nature | 2012

Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations

Brian J. O’Roak; Laura Vives; Santhosh Girirajan; Emre Karakoc; Niklas Krumm; Bradley P. Coe; Roie Levy; Arthur Ko; Choli Lee; Joshua D. Smith; Emily H. Turner; Ian B. Stanaway; Benjamin Vernot; Maika Malig; Carl Baker; Beau Reilly; Joshua M. Akey; Elhanan Borenstein; Mark J. Rieder; Deborah A. Nickerson; Raphael Bernier; Jay Shendure; Evan E. Eichler

It is well established that autism spectrum disorders (ASD) have a strong genetic component; however, for at least 70% of cases, the underlying genetic cause is unknown. Under the hypothesis that de novo mutations underlie a substantial fraction of the risk for developing ASD in families with no previous history of ASD or related phenotypes—so-called sporadic or simplex families—we sequenced all coding regions of the genome (the exome) for parent–child trios exhibiting sporadic ASD, including 189 new trios and 20 that were previously reported. Additionally, we also sequenced the exomes of 50 unaffected siblings corresponding to these new (n = 31) and previously reported trios (n = 19), for a total of 677 individual exomes from 209 families. Here we show that de novo point mutations are overwhelmingly paternal in origin (4:1 bias) and positively correlated with paternal age, consistent with the modest increased risk for children of older fathers to develop ASD. Moreover, 39% (49 of 126) of the most severe or disruptive de novo mutations map to a highly interconnected β-catenin/chromatin remodelling protein network ranked significantly for autism candidate genes. In proband exomes, recurrent protein-altering mutations were observed in two genes: CHD8 and NTNG1. Mutation screening of six candidate genes in 1,703 ASD probands identified additional de novo, protein-altering mutations in GRIN2B, LAMC3 and SCN1A. Combined with copy number variant (CNV) data, these results indicate extreme locus heterogeneity but also provide a target for future discovery, diagnostics and therapeutics.


Nature Genetics | 2011

Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations

Brian J. O'Roak; Pelagia Deriziotis; Choli Lee; Laura Vives; Jerrod J. Schwartz; Santhosh Girirajan; Emre Karakoc; Alexandra P. MacKenzie; Sarah B. Ng; Carl Baker; Mark J. Rieder; Deborah A. Nickerson; Raphael Bernier; Simon E. Fisher; Jay Shendure; Evan E. Eichler

Evidence for the etiology of autism spectrum disorders (ASDs) has consistently pointed to a strong genetic component complicated by substantial locus heterogeneity. We sequenced the exomes of 20 individuals with sporadic ASD (cases) and their parents, reasoning that these families would be enriched for de novo mutations of major effect. We identified 21 de novo mutations, 11 of which were protein altering. Protein-altering mutations were significantly enriched for changes at highly conserved residues. We identified potentially causative de novo events in 4 out of 20 probands, particularly among more severely affected individuals, in FOXP1, GRIN2B, SCN1A and LAMC3. In the FOXP1 mutation carrier, we also observed a rare inherited CNTNAP2 missense variant, and we provide functional support for a multi-hit model for disease risk. Our results show that trio-based exome sequencing is a powerful approach for identifying new candidate genes for ASDs and suggest that de novo mutations may contribute substantially to the genetic etiology of ASDs.


Nature Genetics | 2011

A copy number variation morbidity map of developmental delay

Gregory M. Cooper; Bradley P. Coe; Santhosh Girirajan; Jill A. Rosenfeld; Tiffany H. Vu; Carl Baker; Charles A. Williams; Heather J. Stalker; Rizwan Hamid; Vickie Hannig; Hoda Abdel-Hamid; Patricia I. Bader; Elizabeth McCracken; Dmitriy Niyazov; Kathleen A. Leppig; Heidi Thiese; Marybeth Hummel; Nora Alexander; Jerome L. Gorski; Jennifer Kussmann; Vandana Shashi; Krys Johnson; Catherine Rehder; Blake C. Ballif; Lisa G. Shaffer; Evan E. Eichler

To understand the genetic heterogeneity underlying developmental delay, we compared copy number variants (CNVs) in 15,767 children with intellectual disability and various congenital defects (cases) to CNVs in 8,329 unaffected adult controls. We estimate that ∼14.2% of disease in these children is caused by CNVs >400 kb. We observed a greater enrichment of CNVs in individuals with craniofacial anomalies and cardiovascular defects compared to those with epilepsy or autism. We identified 59 pathogenic CNVs, including 14 new or previously weakly supported candidates, refined the critical interval for several genomic disorders, such as the 17q21.31 microdeletion syndrome, and identified 940 candidate dosage-sensitive genes. We also developed methods to opportunistically discover small, disruptive CNVs within the large and growing diagnostic array datasets. This evolving CNV morbidity map, combined with exome and genome sequencing, will be critical for deciphering the genetic basis of developmental delay, intellectual disability and autism spectrum disorders.


Nature Genetics | 2010

A recurrent 16p12.1 microdeletion supports a two-hit model for severe developmental delay

Santhosh Girirajan; Jill A. Rosenfeld; Gregory M. Cooper; Francesca Antonacci; Priscillia Siswara; Andy Itsara; Laura Vives; Tom Walsh; Shane McCarthy; Carl Baker; Mefford Hc; Jeffrey M. Kidd; Sharon R. Browning; Brian L. Browning; Diane E. Dickel; Deborah L. Levy; Blake C. Ballif; Kathryn Platky; Darren M. Farber; Gordon C. Gowans; Jessica J. Wetherbee; Alexander Asamoah; David D. Weaver; Paul R. Mark; Jennifer N. Dickerson; Bhuwan P. Garg; Sara Ellingwood; Rosemarie Smith; Valerie Banks; Wendy Smith

We report the identification of a recurrent, 520-kb 16p12.1 microdeletion associated with childhood developmental delay. The microdeletion was detected in 20 of 11,873 cases compared with 2 of 8,540 controls (P = 0.0009, OR = 7.2) and replicated in a second series of 22 of 9,254 cases compared with 6 of 6,299 controls (P = 0.028, OR = 2.5). Most deletions were inherited, with carrier parents likely to manifest neuropsychiatric phenotypes compared to non-carrier parents (P = 0.037, OR = 6). Probands were more likely to carry an additional large copy-number variant when compared to matched controls (10 of 42 cases, P = 5.7 × 10−5, OR = 6.6). The clinical features of individuals with two mutations were distinct from and/or more severe than those of individuals carrying only the co-occurring mutation. Our data support a two-hit model in which the 16p12.1 microdeletion both predisposes to neuropsychiatric phenotypes as a single event and exacerbates neurodevelopmental phenotypes in association with other large deletions or duplications. Analysis of other microdeletions with variable expressivity indicates that this two-hit model might be more generally applicable to neuropsychiatric disease.


The New England Journal of Medicine | 2012

Phenotypic Heterogeneity of Genomic Disorders and Rare Copy-Number Variants

Santhosh Girirajan; Jill A. Rosenfeld; Bradley P. Coe; Sumit Parikh; Neil R. Friedman; Amy Goldstein; Robyn A. Filipink; Juliann S. McConnell; Brad Angle; Wendy S. Meschino; Marjan M. Nezarati; Alexander Asamoah; Kelly E. Jackson; Gordon C. Gowans; Judith Martin; Erin P. Carmany; David W. Stockton; Rhonda E. Schnur; Lynette S. Penney; Donna M. Martin; Salmo Raskin; Kathleen A. Leppig; Heidi Thiese; Rosemarie Smith; Erika Aberg; Dmitriy Niyazov; Luis F. Escobar; Dima El-Khechen; Kisha Johnson; Robert Roger Lebel

BACKGROUND Some copy-number variants are associated with genomic disorders with extreme phenotypic heterogeneity. The cause of this variation is unknown, which presents challenges in genetic diagnosis, counseling, and management. METHODS We analyzed the genomes of 2312 children known to carry a copy-number variant associated with intellectual disability and congenital abnormalities, using array comparative genomic hybridization. RESULTS Among the affected children, 10.1% carried a second large copy-number variant in addition to the primary genetic lesion. We identified seven genomic disorders, each defined by a specific copy-number variant, in which the affected children were more likely to carry multiple copy-number variants than were controls. We found that syndromic disorders could be distinguished from those with extreme phenotypic heterogeneity on the basis of the total number of copy-number variants and whether the variants are inherited or de novo. Children who carried two large copy-number variants of unknown clinical significance were eight times as likely to have developmental delay as were controls (odds ratio, 8.16; 95% confidence interval, 5.33 to 13.07; P=2.11×10(-38)). Among affected children, inherited copy-number variants tended to co-occur with a second-site large copy-number variant (Spearman correlation coefficient, 0.66; P<0.001). Boys were more likely than girls to have disorders of phenotypic heterogeneity (P<0.001), and mothers were more likely than fathers to transmit second-site copy-number variants to their offspring (P=0.02). CONCLUSIONS Multiple, large copy-number variants, including those of unknown pathogenic significance, compound to result in a severe clinical presentation, and secondary copy-number variants are preferentially transmitted from maternal carriers. (Funded by the Simons Foundation Autism Research Initiative and the National Institutes of Health.).


American Journal of Human Genetics | 2012

De Novo Pathogenic SCN8A Mutation Identified by Whole-Genome Sequencing of a Family Quartet Affected by Infantile Epileptic Encephalopathy and SUDEP

Krishna R. Veeramah; Janelle E. O'Brien; Miriam H. Meisler; Xiaoyang Cheng; Sulayman D. Dib-Hajj; Stephen G. Waxman; Dinesh Talwar; Santhosh Girirajan; Evan E. Eichler; Linda L. Restifo; Robert P. Erickson; Michael F. Hammer

Individuals with severe, sporadic disorders of infantile onset represent an important class of disease for which discovery of the underlying genetic architecture is not amenable to traditional genetic analysis. Full-genome sequencing of affected individuals and their parents provides a powerful alternative strategy for gene discovery. We performed whole-genome sequencing (WGS) on a family quartet containing an affected proband and her unaffected parents and sibling. The 15-year-old female proband had a severe epileptic encephalopathy consisting of early-onset seizures, features of autism, intellectual disability, ataxia, and sudden unexplained death in epilepsy. We discovered a de novo heterozygous missense mutation (c.5302A>G [p.Asn1768Asp]) in the voltage-gated sodium-channel gene SCN8A in the proband. This mutation alters an evolutionarily conserved residue in Nav1.6, one of the most abundant sodium channels in the brain. Analysis of the biophysical properties of the mutant channel demonstrated a dramatic increase in persistent sodium current, incomplete channel inactivation, and a depolarizing shift in the voltage dependence of steady-state fast inactivation. Current-clamp analysis in hippocampal neurons transfected with p.Asn1768Asp channels revealed increased spontaneous firing, paroxysmal-depolarizing-shift-like complexes, and an increased firing frequency, consistent with a dominant gain-of-function phenotype in the heterozygous proband. This work identifies SCN8A as the fifth sodium-channel gene to be mutated in epilepsy and demonstrates the value of WGS for the identification of pathogenic mutations causing severe, sporadic neurological disorders.


Annual Review of Genetics | 2011

Human Copy Number Variation and Complex Genetic Disease

Santhosh Girirajan; Catarina D. Campbell; Evan E. Eichler

Copy number variants (CNVs) play an important role in human disease and population diversity. Advancements in technology have allowed for the analysis of CNVs in thousands of individuals with disease in addition to thousands of controls. These studies have identified rare CNVs associated with neuropsychiatric diseases such as autism, schizophrenia, and intellectual disability. In addition, copy number polymorphisms (CNPs) are present at higher frequencies in the population, show high diversity in copy number, sequence, and structure, and have been associated with multiple phenotypes, primarily related to immune or environmental response. However, the landscape of copy number variation still remains largely unexplored, especially for smaller CNVs and those embedded within complex regions of the human genome. An integrated approach including characterization of single nucleotide variants and CNVs in a large number of individuals with disease and normal genomes holds the promise of thoroughly elucidating the genetic basis of human disease and diversity.


PLOS Genetics | 2011

Relative Burden of Large CNVs on a Range of Neurodevelopmental Phenotypes

Santhosh Girirajan; Zoran Brkanac; Bradley P. Coe; Carl Baker; Laura Vives; Tiffany H. Vu; Neil Shafer; Raphael Bernier; Giovanni Battista Ferrero; Margherita Silengo; Stephen T. Warren; Carlos S. Moreno; Marco Fichera; Corrado Romano; Wendy H. Raskind; Evan E. Eichler

While numerous studies have implicated copy number variants (CNVs) in a range of neurological phenotypes, the impact relative to disease severity has been difficult to ascertain due to small sample sizes, lack of phenotypic details, and heterogeneity in platforms used for discovery. Using a customized microarray enriched for genomic hotspots, we assayed for large CNVs among 1,227 individuals with various neurological deficits including dyslexia (376), sporadic autism (350), and intellectual disability (ID) (501), as well as 337 controls. We show that the frequency of large CNVs (>1 Mbp) is significantly greater for ID–associated phenotypes compared to autism (p = 9.58×10−11, odds ratio = 4.59), dyslexia (p = 3.81×10−18, odds ratio = 14.45), or controls (p = 2.75×10−17, odds ratio = 13.71). There is a striking difference in the frequency of rare CNVs (>50 kbp) in autism (10%, p = 2.4×10−6, odds ratio = 6) or ID (16%, p = 3.55×10−12, odds ratio = 10) compared to dyslexia (2%) with essentially no difference in large CNV burden among dyslexia patients compared to controls. Rare CNVs were more likely to arise de novo (64%) in ID when compared to autism (40%) or dyslexia (0%). We observed a significantly increased large CNV burden in individuals with ID and multiple congenital anomalies (MCA) compared to ID alone (p = 0.001, odds ratio = 2.54). Our data suggest that large CNV burden positively correlates with the severity of childhood disability: ID with MCA being most severely affected and dyslexics being indistinguishable from controls. When autism without ID was considered separately, the increase in CNV burden was modest compared to controls (p = 0.07, odds ratio = 2.33).


Human Molecular Genetics | 2010

Phenotypic variability and genetic susceptibility to genomic disorders

Santhosh Girirajan; Evan E. Eichler

The duplication architecture of the human genome predisposes our species to recurrent copy number variation and disease. Emerging data suggest that this mechanism of mutation contributes to both common and rare diseases. Two features regarding this form of mutation have emerged. First, common structural polymorphisms create susceptible and protective chromosomal architectures. These structural polymorphisms occur at varying frequencies in populations, leading to different susceptibility and ethnic predilection. Second, a subset of rearrangements shows extreme variability in expressivity. We propose that two types of genomic disorders may be distinguished: syndromic forms where the phenotypic features are largely invariant and those where the same molecular lesion associates with a diverse set of diagnoses including epilepsy, schizophrenia, autism, intellectual disability and congenital malformations. Copy number variation analyses of patient genomes reveal that disease type and severity may be explained by the occurrence of additional rare events and their inheritance within families. We propose that the overall burden of copy number variants creates differing sensitized backgrounds during development leading to different thresholds and disease outcomes. We suggest that the accumulation of multiple high-penetrant alleles of low frequency may serve as a more general model for complex genetic diseases, posing a significant challenge for diagnostics and disease management.


Nature | 2009

A burst of segmental duplications in the genome of the African great ape ancestor

Tomas Marques-Bonet; Jeffrey M. Kidd; Mario Ventura; Tina Graves; Ze Cheng; LaDeanna W. Hillier; Zhaoshi Jiang; Carl Baker; Ray Malfavon-Borja; Lucinda A. Fulton; Can Alkan; Gozde Aksay; Santhosh Girirajan; Priscillia Siswara; Lin Chen; Maria Francesca Cardone; Arcadi Navarro; Elaine R. Mardis; Richard Wilson; Evan E. Eichler

It is generally accepted that the extent of phenotypic change between human and great apes is dissonant with the rate of molecular change. Between these two groups, proteins are virtually identical, cytogenetically there are few rearrangements that distinguish ape–human chromosomes, and rates of single-base-pair change and retrotransposon activity have slowed particularly within hominid lineages when compared to rodents or monkeys. Studies of gene family evolution indicate that gene loss and gain are enriched within the primate lineage. Here, we perform a systematic analysis of duplication content of four primate genomes (macaque, orang-utan, chimpanzee and human) in an effort to understand the pattern and rates of genomic duplication during hominid evolution. We find that the ancestral branch leading to human and African great apes shows the most significant increase in duplication activity both in terms of base pairs and in terms of events. This duplication acceleration within the ancestral species is significant when compared to lineage-specific rate estimates even after accounting for copy-number polymorphism and homoplasy. We discover striking examples of recurrent and independent gene-containing duplications within the gorilla and chimpanzee that are absent in the human lineage. Our results suggest that the evolutionary properties of copy-number mutation differ significantly from other forms of genetic mutation and, in contrast to the hominid slowdown of single-base-pair mutations, there has been a genomic burst of duplication activity at this period during human evolution.

Collaboration


Dive into the Santhosh Girirajan's collaboration.

Top Co-Authors

Avatar
Top Co-Authors

Avatar

Sarah H. Elsea

Baylor College of Medicine

View shared research outputs
Top Co-Authors

Avatar

Jill A. Rosenfeld

Baylor College of Medicine

View shared research outputs
Top Co-Authors

Avatar

Carl Baker

University of Washington

View shared research outputs
Top Co-Authors

Avatar

Bradley P. Coe

University of Washington

View shared research outputs
Top Co-Authors

Avatar

Andrew Polyak

Pennsylvania State University

View shared research outputs
Top Co-Authors

Avatar

Lucilla Pizzo

Pennsylvania State University

View shared research outputs
Top Co-Authors

Avatar

Matthew Jensen

Pennsylvania State University

View shared research outputs
Top Co-Authors

Avatar
Top Co-Authors

Avatar
Researchain Logo
Decentralizing Knowledge