Dr. Siddharth (“Sid”) Srivastava is the recipient 2023 Philip R. Dodge Young Investigator Award. This award recognizes his service, innovation, generosity, and impact on the field of child neurology, specifically in the areas of neurogenetics and cerebral palsy (CP).
Sid was born in Delhi, India, and moved to the US as a toddler. His father’s academic teaching career took their family to Raleigh, NC, then to New Paltz, NY, and finally to Baton Rouge, LA, where Sid grew up from age 6 until college. Sid obtained his B.A. in Biochemistry from Columbia University. He went on to medical school at the Johns Hopkins School of Medicine, where he received his M.D. as well as the award for excellence in medical student research. Sid deepened his keen interest in neurogenetic disorders and completed his residency in Pediatrics at Johns Hopkins and Child Neurology and Neurodevelopmental Disabilities (NDD) at the Kennedy Krieger Institute. This was just the beginning of what has blossomed into a career focused on neurogenetics that blends patient care with patient-oriented research.
Early research and clinical impact on genetic neurodevelopmental disorders
Sid’s research during NDD training focused on delineating the clinical spectrum and natural history of several neurodevelopmental disorders. His early work is exemplified by his 2014 article on clinical whole exome sequencing for childhood neurological disorders, which was selected as one of the best advances in the field of neurogenetics by Neurology Today. Sid’s robust foundation of clinical training and astute observations led him to delineate the phenotypes of many important neurogenetic syndromes (e.g., BRAT1, HIVEP2, PTEN, SHANK3), creating a path toward future clinical trials with well-defined genetic conditions and well-defined outcome measures. In the rare disease space, Sid’s reports, for example, his paper with Dr. Sakkubai Naidu and team on the gene BRAT1 (Srivastava et al., Am J Med Genet, 2016), provide such an invaluable resource to those of us seeing patients with these rare conditions. Following his pediatrics and NDD training, Sid pursued a neurogenetics fellowship at Boston Children’s Hospital, supported through an NIH T32 grant.
During his neurogenetics fellowship, in addition to research, Sid immersed himself in various neurogenetics clinics and saw patients with tuberous sclerosis complex, brain malformations, genetic epilepsies, and unknown but suspected genetic disorders. He was noted to demonstrate clinical excellence, compassion, and collegiality in our multidisciplinary clinics. He also brought his neurodevelopmental training to our patients – what a gift it was to have Sid as part of any clinic, as he provided real-time neurodevelopmental evaluation and offered advice to parents of children with often newly diagnosed neurogenetic syndromes.
Sid’s research in neurogenetics impacts both precision diagnosis and precision treatment. In 2018, Sid contributed to a consensus development conference in Boston focused on the molecular diagnostic yield of exome sequencing for NDDs. He was the first author of the resulting manuscript, “Meta-analysis and multidisciplinary consensus statement: exome sequencing is a first-tier clinical diagnostic test for individuals with neurodevelopmental disorders,” which was published in Genetics in Medicine. The recommendations of this report have been echoed by the evidence-based clinical guideline of the American College of Medical Genetics and Genomics (ACMG) in 2021. He has also been working closely with several patient advocacy groups such as PMS Foundation, PTEN Research, iDefine, and his work was crucially instrumental in the approval of an ICD-10 code by the CDC for Kleefstra Syndrome, which is going to accelerate research in this ultra-rare disorder. Finally, Sid’s active role in the NIH-supported Developmental Synaptopathies Consortium has led to highly significant results, including the first clinical trial examining the effects of mTOR inhibitors on neurocognition in individuals with PTEN Hamartoma Tumor Syndrome (Srivastava et al., Human Molecular Genetics, 2022) and the “Updated consensus guidelines on the management of Phelan-McDermid syndrome” (Srivastava et al., Human Am J Med Genet A., 2023).
Genetics of CP – changing the landscape of CP and changing clinical practice
Sid’s insightful observations that a great many patients who are labeled as having “CP” may not actually meet strict definitions of CP formed the kernel of his current very active phenotype-genotype project, now supported by a K23 award from the NINDS with institutional support for trio exome sequencing from our Boston Children’s Hospital Rare Disease Cohorts (CRDC) Initiative. Since many patients referred to Sid and his clinical colleagues in our Cerebral Palsy Program have what is classified as ‘atypical CP,’ Sid raised the question about their etiologies and challenged the assumption that is prevalent among many individuals that all CP is acquired.
Sid’s path to uncover the genetics of CP has already started to transform the field of CP, long thought to be exclusively acquired and not genetic. Sid rapidly established an efficient and productive clinical research team, enrolling patients, performing rigorous research-level phenotyping that includes the precise delineation of phenotypic features, and conducting state-of-the-art genomic analyses. The first 50 patients sequenced from his clinic demonstrated a 25% diagnostic yield, with results that Sid delivered back to the families. This is on par with the diagnostic yield of cohorts with epilepsy, autism spectrum disorder, and intellectual disability and were published with Sid as co-senior author (Chopra, Gable, et al., ACTN, 2021). Sid’s is one of only a few well-phenotyped cohorts of patients with verified CP, and the results have led to clinical impact locally already as well as independent collaborations between Sid and bench scientists at Boston Children’s and other hospitals around the country. Sid’s work brings a critically important level of rigor to push the field of CP genetics forward, and he has engaged actively with others in the field, including his K23 Co-Mentor, Dr. Michael Kruer, and last year’s Dodge Award recipient, Dr. Bhooma Aravamuthan.
Sid’s CP exome sequencing cohort now includes more than 250 individuals. This is an extraordinary number for such a short period of time and a testament to the true integration of his clinical practice with his research. Preliminary analysis has shown a molecular diagnosis in approximately 20% of his cohort, representing a wide spectrum of different biological pathways. He continues to collaborate with internal and outside partners delineating the phenotype of neurodevelopmental disorders including CP. He has most recently delineated a novel human disease gene, SPTSSA, implicated in a phenotype of complex hereditary spastic paraplegia (Srivastava et al., Brain, 2023). He has conducted a meta-analysis highlighting the diagnostic yield of exome sequencing and chromosomal microarray for CP, recently published in JAMA Neurology (Srivastava et al., 2022), demonstrating the generalizability of the research he and others are conducting and serving as the basis for evolving clinical practice guidelines for child neurologists seeing patients with CP.
Academic productivity, impact, and future promise
Over his relatively short career so far, Dr. Srivastava has had stellar productivity. This example is one from among 70 papers related to neurogenetics (25 of them first-author, including in high-impact journals, such as Annals of Neurology, Brain, and JAMA Neurology). Sid’s publication record is remarkable on its own but even more so given that he started his career with a heavy clinical workload, and with great discipline and maturity, he has found a balance between honoring his commitment to our patients with CP and pursuing his critically important research. In 2014 and 2015, Sid was awarded an Outstanding Junior Member award from the Child Neurology Society. In 2020, Sid was promoted to Assistant Professor in Neurology at Harvard Medical School, a position he currently holds today.
Finally, Sid is incredibly thoughtful, collaborative, and kind. His resilience through the pandemic is exemplified by his impressive willingness to step up and help anyone and by his continued academic productivity. Sid and his wife, also a physician, have three young children. Sid has a genuine passion for working with families of children with developmental disabilities and complex disorders and bestows kindness and devotion to his patients and colleagues the way he does to his own family. He is actively engaged in training residents and students and embraces collaborations with a spirit of inclusiveness. His infectious enthusiasm for patient-oriented research has led to several residents and students seeking him out for mentorship, and Sid has indeed provided both content expertise and academic mentoring to all who come his way. His exceptional level of involvement in such a wide range of clinical, academic, and mentoring activities is a testament to his dedication to bringing science and scholarship to influence practice in the field of child neurology. Sid’s commitment to improve the lives of his patients and patients everywhere with childhood neurodevelopmental disorders is matched by his great potential for continued success, impact, and leadership in the field.