Dong Li1, Alanna Strong1,2, Kaitlyn M Shen1, David Cassiman3, Maria Van Dyck4, Natalia Duarte Linhares5, Eugenia Ribeiro Valadares6, Tiancheng Wang1, Sergio D J Pena5,7, Jaak Jaeken3, Samantha Vergano8,9, Elaine Zackai2, Anne Hing10, Penny Chow10, Arupa Ganguly11, Tasja Scholz12, Tatjana Bierhals12, Deindl Philipp13, Hakon Hakonarson1,2, Elizabeth Bhoj14,15. 1. Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA. 2. Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA. 3. University Hospitals and University of Leuven, Metabolic Center, Leuven, Belgium. 4. University Hospitals and University of Leuven, Pediatric Nephrology, Leuven, Belgium. 5. Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil. 6. CENTRARE-Centro de Referência em fendas orofaciais, Fundação Benjamin Guimarães-Hospital da Baleia, Belo Horizonte, Brazil. 7. Laboratório Gene-Núcleo de Genética Médica, Belo Horizonte, Brazil. 8. Division of Medical Genetics and Metabolism, Children's Hospital of The King's Daughters, Norfolk, VA, USA. 9. Department of Pediatrics, Eastern Virginia Medical School, Norfolk, VA, USA. 10. Division of Genetics, Seattle Children's Hospital, Seattle, WA, USA. 11. Department of Genetics, The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. 12. Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 13. Department of Neonatology and Pediatric Intensive Care Medicine, University Children's Hospital, University Medical Center Hamburg Eppendorf, Hamburg, Germany. 14. Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA. bhoje@email.chop.edu. 15. Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA. bhoje@email.chop.edu.
Abstract
PURPOSE: Hardikar syndrome (MIM 612726) is a rare multiple congenital anomaly syndrome characterized by facial clefting, pigmentary retinopathy, biliary anomalies, and intestinal malrotation, but with preserved cognition. Only four patients have been reported previously, and none had a molecular diagnosis. Our objective was to identify the genetic basis of Hardikar syndrome (HS) and expand the phenotypic spectrum of this disorder. METHODS: We performed exome sequencing on two previously reported and five unpublished female patients with a clinical diagnosis of HS. X-chromosome inactivation (XCI) studies were also performed. RESULTS: We report clinical features of HS with previously undescribed phenotypes, including a fatal unprovoked intracranial hemorrhage at age 21. We additionally report the discovery of de novo pathogenic nonsense and frameshift variants in MED12 in these seven individuals and evidence of extremely skewed XCI in all patients with informative testing. CONCLUSION: Pathogenic missense variants in the X-chromosome gene MED12 have previously been associated with Opitz-Kaveggia syndrome, Lujan syndrome, Ohdo syndrome, and nonsyndromic intellectual disability, primarily in males. We propose a fifth, female-specific phenotype for MED12, and suggest that nonsense and frameshift loss-of-function MED12 variants in females cause HS. This expands the MED12-associated phenotype in females beyond intellectual disability.
PURPOSE: Hardikar syndrome (MIM 612726) is a rare multiple congenital anomaly syndrome characterized by facial clefting, pigmentary retinopathy, biliary anomalies, and intestinal malrotation, but with preserved cognition. Only four patients have been reported previously, and none had a molecular diagnosis. Our objective was to identify the genetic basis of Hardikar syndrome (HS) and expand the phenotypic spectrum of this disorder. METHODS: We performed exome sequencing on two previously reported and five unpublished female patients with a clinical diagnosis of HS. X-chromosome inactivation (XCI) studies were also performed. RESULTS: We report clinical features of HS with previously undescribed phenotypes, including a fatal unprovoked intracranial hemorrhage at age 21. We additionally report the discovery of de novo pathogenic nonsense and frameshift variants in MED12 in these seven individuals and evidence of extremely skewed XCI in all patients with informative testing. CONCLUSION: Pathogenic missense variants in the X-chromosome gene MED12 have previously been associated with Opitz-Kaveggia syndrome, Lujan syndrome, Ohdo syndrome, and nonsyndromic intellectual disability, primarily in males. We propose a fifth, female-specific phenotype for MED12, and suggest that nonsense and frameshift loss-of-function MED12 variants in females cause HS. This expands the MED12-associated phenotype in females beyond intellectual disability.
Authors: Nishitha R Pillai; Dana Miller; Grace Bronken; Amrita Kahlon Salunke; Anjali Aggarwal Journal: Am J Med Genet A Date: 2022-04-06 Impact factor: 2.578