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Kabuki syndrome

Kabuki syndrome (KS) is a heterogeneous group of congenital malformation disorders that follow a continuous phenotypic spectrum. Patients with KS present with various severity of intellectual disability, hearing loss, hypotonia, cardiac and renal anomalies as well as short stature.  KS is due to dominant-negative mutations in autosomal KMT2D (80% of cases) or X-linked KDM6A, respectively. KMT2D is a lysine methyltransferase that adds a mark promoting gene transcription.  Most of the KMT2D variants identified in patients with KS are de-novo missense variants predicted to result in haplo-insufficiency of enzyme function. KDM6A is a lysine demethylase that removes repressive methylation to allow gene expression. A small number of individuals with KS have mutations in KDM6A, again as a result of overall decreased enzyme function. Importantly, KDM6A has been reported to escape X-inactivation, supporting the hypothesis that haplo-insufficiency of the enzyme may also result in disease.  Thus, KS is caused by primary mutations in one of at least two identified distinct epigenetic regulators.  Mutations in either of these genes are not compensated for by hyperactivity of the other regulator, suggesting common as well as non-overlapping function(s) of these enzymes.

An interdisciplinary program for epigenomic disorders with a primary focus on KS within the Division of Genetics and Genomics at Boston Children’s Hospital was established in 2017 (The Roya Kabuki Program; director Olaf Bodamer MD PhD). The main objectives of this program are to 1) deep phenotype affected individuals using a clinical and multi-OMICS approach; 2) standardize management through a multi-disciplinary team and 3) participate in clinical trials for novel therapies to address unmet needs. To learn more about this initiative please visit

Lysosomal disorders

Dr. Bodamer has a long-standing research interest and clinical expertise in lysosomal storage disorders. He called into life the Boston Lysosomal Diseases (BoLD) program at Boston Children’s Hospital, which aims at providing coordinated, state-of-the art clinical care for patients with lysosomal storage disorders. In addition, he is actively involved in various clinical trials and member of several scientific advisory boards for pharmaceutical companies and the NPC foundation.

Niemann-Pick type C

Niemann-Pick disease type C (NPC; OMIM 257220) is a disorder of intralysosomal cholesterol trafficking due to compound heterozygous or homozygous mutations in either the NPC1 (95%) or NPC2 (5%) gene, respectively. The NPC1 gene encodes a membrane protein which has several domains that are homologous to other integral membrane proteins that respond to cell cholesterol content.  The NPC1 protein is a necessary component for intracellular trafficking of LDL-derived cholesterol. In contrast, the gene responsible for NPC2, known as the HE1 gene, encodes a lysosomal glycoprotein that is present in many tissues, and its function and role in NPC2 is still not confirmed.

Progressive accumulation of unesterified cholesterol and related lipids results in a continuous spectrum of clinical phenotype ranging from prenatal onset, severe disease to late, adult-onset milder disease. Neonatal and infantile NPC presents with jaundice and hepatosplenomegaly, and many of the patients become symptom free but some die in the first 6 months of age due to liver failure. Childhood NPC, which is the classical presentation of the disease, presents with asymptomatic hepatosplenomegaly and progressive neurological deficits. Lastly, adult-onset NPC typically presents with neurological dysfunction at a slower rate of progression, and older patients may present with psychosis or other psychiatric illnesses. The rate of neurocognitive decline is variable depending on NPC genotype, ancestry and other yet un-identified genetic modifier. NPC is a pan-ethnic disorder with an estimated incidence rate of between 1/150,000 and 1/1,000,000 live births. There continues to be an unmet therapeutic need that needs to be urgently addressed by strategies that target the underlying genetic defect and/or disease mechanism. Our laboratory is actively pursuing the development of a mRNA therapeutic strategy through a partnership with a pharmaceutical company.

Precision Medicine and Preterm Birth (PMAP) study

We currently collect longitudinal data on the complex interplay of the environment, microbiome, proteome, metabolome, transcriptome, methylome and genome during term and preterm pregnancies, and post-natal infancy to understand the pathophysiology of preterm birth using a systems biology approach.

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