Hardikar syndrome is an extremely rare genetic disorder that occurs in girls. With a handful of known patients worldwide, clinicians have found providing treatment recommendations and developing therapeutic options to be challenging. However, a new paper from researchers at Children’s Hospital of Philadelphia (CHOP) offers a critical update, describing an innovative standard-of-care based on insights from large cohort studies that account for previously undescribed cardiac and vascular symptoms. Additionally, the study reports new laboratory discoveries that implicate distinct genetic pathways in the disease that existing drugs can target. The findings were recently published in the journal Genetics in Medicine.
Hardikar syndrome was first described in 1992 as a novel syndrome characterized by cleft lip/palate, pigmentary retinopathy, intestinal malrotation, hepatobiliary disease, and genitourinary malformations. A prior study led by CHOP researchers in 2021 found that nonsense and frameshift variants in the X-linked gene MED12 cause Hardikar syndrome. This research reported the largest patient cohort to date – 7 patients – but the small sample size left many questions unanswered, including mysteries surrounding the full clinical spectrum of Hardikar syndrome and what drives disease pathology. Motivated by the new gene discovery, a growing patient community worked closely with the researchers to provide a deeper understanding of the disorder.
“Families from all over the world shared their stories, which provided incredible insight into the disease and , helped inform new clinical recommendations,” said first study author Alanna Strong, MD, PhD, an Assistant Professor in the Division of Human Genetics at CHOP. “These insights also helped guide our laboratory studies to get a better sense of what’s happening at the molecular level. The combination of the clinical and laboratory knowledge we gained in this collaboration led us to redirect our efforts and focus more on the severe vascular complications facing these patients.”
In this new study, which includes data from 11 previously unreported Hardikar syndrome patients, researchers identified a variety of cardiac symptoms, including cardiomyopathy, arrhythmia, and vascular anomalies, that had not been previously described in association with Hardikar syndrome. The study also demonstrated a new type of causal MED12 variant – those affecting splice sites – which can affect the way RNA is put together to ultimately make protein.
The study also examined the basic science behind the disorder, where researchers reported dysregulated cell ciliation, hedgehog signaling, and YAP signaling with MED12 deficiency. These are all critical developmental pathways, with YAP and hedgehog pathways known to be involved in vascular development.
The hedgehog and YAP pathways are already being explored as therapeutic targets for cancer. Upcoming studies of Hardikar syndrome will use preclinical models to determine how MED12 deficiency leads to vascular malformations, which could help determine if existing drugs could be repurposed to treat Hardikar patients.
“The study demonstrates how the work we do, which delves much deeper than clinical testing, allows us to study variants that can provide a link to the phenotypes reported by patients, even with an ultra-rare disease such as Hardikar syndrome,” said senior study author Hakon Hakonarson, MD, PhD, Professor of Pediatrics and Director of the Center for Applied Genomics (CAG) at CHOP.
This study was supported by K08 Mentored Career Development Award K08DK128606 and the Institutional Development Fund.
Strong et al, “Novel insights into the phenotypic spectrum and pathogenesis of Hardikar syndrome.” Genet Med. Online July 20, 2024. DOI: 10.1016/j.gim.2024.101222.
Hardikar syndrome is an extremely rare genetic disorder that occurs in girls. With a handful of known patients worldwide, clinicians have found providing treatment recommendations and developing therapeutic options to be challenging. However, a new paper from researchers at Children’s Hospital of Philadelphia (CHOP) offers a critical update, describing an innovative standard-of-care based on insights from large cohort studies that account for previously undescribed cardiac and vascular symptoms. Additionally, the study reports new laboratory discoveries that implicate distinct genetic pathways in the disease that existing drugs can target. The findings were recently published in the journal Genetics in Medicine.
Hardikar syndrome was first described in 1992 as a novel syndrome characterized by cleft lip/palate, pigmentary retinopathy, intestinal malrotation, hepatobiliary disease, and genitourinary malformations. A prior study led by CHOP researchers in 2021 found that nonsense and frameshift variants in the X-linked gene MED12 cause Hardikar syndrome. This research reported the largest patient cohort to date – 7 patients – but the small sample size left many questions unanswered, including mysteries surrounding the full clinical spectrum of Hardikar syndrome and what drives disease pathology. Motivated by the new gene discovery, a growing patient community worked closely with the researchers to provide a deeper understanding of the disorder.
“Families from all over the world shared their stories, which provided incredible insight into the disease and , helped inform new clinical recommendations,” said first study author Alanna Strong, MD, PhD, an Assistant Professor in the Division of Human Genetics at CHOP. “These insights also helped guide our laboratory studies to get a better sense of what’s happening at the molecular level. The combination of the clinical and laboratory knowledge we gained in this collaboration led us to redirect our efforts and focus more on the severe vascular complications facing these patients.”
In this new study, which includes data from 11 previously unreported Hardikar syndrome patients, researchers identified a variety of cardiac symptoms, including cardiomyopathy, arrhythmia, and vascular anomalies, that had not been previously described in association with Hardikar syndrome. The study also demonstrated a new type of causal MED12 variant – those affecting splice sites – which can affect the way RNA is put together to ultimately make protein.
The study also examined the basic science behind the disorder, where researchers reported dysregulated cell ciliation, hedgehog signaling, and YAP signaling with MED12 deficiency. These are all critical developmental pathways, with YAP and hedgehog pathways known to be involved in vascular development.
The hedgehog and YAP pathways are already being explored as therapeutic targets for cancer. Upcoming studies of Hardikar syndrome will use preclinical models to determine how MED12 deficiency leads to vascular malformations, which could help determine if existing drugs could be repurposed to treat Hardikar patients.
“The study demonstrates how the work we do, which delves much deeper than clinical testing, allows us to study variants that can provide a link to the phenotypes reported by patients, even with an ultra-rare disease such as Hardikar syndrome,” said senior study author Hakon Hakonarson, MD, PhD, Professor of Pediatrics and Director of the Center for Applied Genomics (CAG) at CHOP.
This study was supported by K08 Mentored Career Development Award K08DK128606 and the Institutional Development Fund.
Strong et al, “Novel insights into the phenotypic spectrum and pathogenesis of Hardikar syndrome.” Genet Med. Online July 20, 2024. DOI: 10.1016/j.gim.2024.101222.