Rare Disease

Advancing Understanding
of Rare Disease

Annually, up to 10 percent of the nearly 4 million babies born in the US are hospitalized in an intensive care unit due to an underlying rare genetic disease. Without proper diagnosis and treatment, some such disorders can lead to permanent disability or even death.

Many rare genetic diseases are never seen by most physicians, as they affect very few children worldwide. This creates challenges in recognizing the condition and knowing how to treat it.

At RCIGM, we want to provide accurate information when a rare disorder is diagnosed to enable families and their healthcare teams to make informed decisions about treatment. 

Knowledge Generation

  • We identify new diseases.
  • We study the normal disease progression of the rare diseases we diagnose.
  • We evaluate treatments for rare disease, including trying medicines not previously used in children, and participating in research with drug companies to evaluate the efficacy of potential new therapies.

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Key Facts

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Publications

Nat Commun. 2023 Nov 1;14(1):6770. doi: 10.1038/s41467-023-42150-4.

ABSTRACT

Type I interferon (IFN) signalling is tightly controlled. Upon recognition of DNA by cyclic GMP-AMP synthase (cGAS), stimulator of interferon genes (STING) translocates along the endoplasmic reticulum (ER)-Golgi axis to induce IFN signalling. Termination is achieved through autophagic degradation or recycling of STING by retrograde Golgi-to-ER transport. Here, we identify the GTPase ADP-ribosylation factor 1 (ARF1) as a crucial negative regulator of cGAS-STING signalling. Heterozygous ARF1 missense mutations cause a previously unrecognized type I interferonopathy associated with enhanced IFN-stimulated gene expression. Disease-associated, GTPase-defective ARF1 increases cGAS-STING dependent type I IFN signalling in cell lines and primary patient cells. Mechanistically, mutated ARF1 perturbs mitochondrial morphology, causing cGAS activation by aberrant mitochondrial DNA release, and leads to accumulation of active STING at the Golgi/ERGIC due to defective retrograde transport. Our data show an unexpected dual role of ARF1 in maintaining cGAS-STING homeostasis, through promotion of mitochondrial integrity and STING recycling.

PMID:37914730 | DOI:10.1038/s41467-023-42150-4

JACC Case Rep. 2023 Feb 22;11:101790. doi: 10.1016/j.jaccas.2023.101790. eCollection 2023 Apr 5.

ABSTRACT

We present a 22-week fetus with isolated absent aortic valve and inverse circular shunt. The pregnancy was interrupted. Here, echocardiography and pathology images demonstrate this rare entity. Whole genome sequencing revealed a potentially disease-causing variant in the APC gene. Whole genome sequencing should be considered in severe and rare fetal diseases. (Level of Difficulty: Advanced.).

PMID:37077433 DOI:10.1016/j.jaccas.2023.101790

PLoS One. 2023 Jan 26;18(1):e0279430. doi: 10.1371/journal.pone.0279430. eCollection 2023.

ABSTRACT

Short Tandem Repeats (STRs) have been found to play a role in a myriad of complex traits and genetic diseases. We examined the variability in the lengths of over 850,000 STR loci in 996 children with suspected genetic disorders and 1,178 parents across six separate ancestral groups: Africans, Europeans, East Asians, Admixed Americans, Non-admixed Americans, and Pacific Islanders. For each STR locus we compared allele length between and within each ancestry group. In relation to Europeans, admixed Americans had the most similar STR lengths with only 623 positions either significantly expanded or contracted, while the divergence was highest in Africans, with 4,933 chromosomal positions contracted or expanded. We also examined probands to identify STR expansions at known pathogenic loci. The genes TCF4, AR, and DMPK showed significant expansions with lengths 250% greater than their various average allele lengths in 49, 162, and 11 individuals respectively. All 49 individuals containing an expansion in TCF4 and six individuals containing an expansion in DMPK presented with allele lengths longer than the known pathogenic length for these genes. Next, we identified individuals with significant expansions in highly conserved loci across all ancestries. Eighty loci in conserved regions met criteria for divergence. Two of these individuals were found to have exonic STR expansions: one in ZBTB4 and the other in SLC9A7, which is associated with X-linked mental retardation. Finally, we used parent-child trios to detect and analyze de novo mutations. In total, we observed 3,219 de novo expansions, where proband allele lengths are greater than twice the longest parental allele length. This work helps lay the foundation for understanding STR lengths genome-wide across ancestries and may help identify new disease genes and novel mechanisms of pathogenicity in known disease genes.

PMID:36701310 DOI:10.1371/journal.pone.0279430

Am J Med Genet C Semin Med Genet. 2023 Jan 24. doi: 10.1002/ajmg.c.32029. Online ahead of print.

ABSTRACT

The cost and time needed to conduct whole-genome sequencing (WGS) have decreased significantly in the last 20 years. At the same time, the number of conditions with a known molecular basis has steadily increased, as has the number of investigational new drug applications for novel gene-based therapeutics. The prospect of precision gene-targeted therapy for all seems in reach… or is it? Here we consider practical and strategic considerations that need to be addressed to establish a foundation for the early, effective, and equitable delivery of these treatments.

PMID:36691939 DOI:10.1002/ajmg.c.32029

Am J Med Genet A. 2023 Jan 18. doi: 10.1002/ajmg.a.63097. Online ahead of print.

ABSTRACT

Increasing use of unbiased genomic sequencing in critically ill infants can expand understanding of rare diseases such as Kabuki syndrome (KS). Infants diagnosed with KS through genome-wide sequencing performed during the initial hospitalization underwent retrospective review of medical records. Human phenotype ontology terms used in genomic analysis were aggregated and analyzed. Clinicians were surveyed regarding changes in management and other care changes. Fifteen infants met inclusion criteria. KS was not suspected prior to genomic sequencing. Variants were classified as Pathogenic (n = 10) or Likely Pathogenic (n = 5) by American College of Medical Genetics and Genomics Guidelines. Fourteen variants were de novo (KMT2D, n = 12, KDM6A, n = 2). One infant inherited a likely pathogenic variant in KMT2D from an affected father. Frequent findings involved cardiovascular (14/15) and renal (7/15) systems, with palatal defects also identified (6/15). Three infants had non-immune hydrops. No minor anomalies were universally documented; ear anomalies, micrognathia, redundant nuchal skin, and hypoplastic nails were common. Changes in management were reported in 14 infants. Early use of unbiased genome-wide sequencing enabled a molecular diagnosis prior to clinical recognition including infants with atypical or rarely reported features of KS while also expanding the phenotypic spectrum of this rare disorder.

PMID:36651673 DOI:10.1002/ajmg.a.63097

Nat Commun. 2022 Jul 26;13(1):4057. doi: 10.1038/s41467-022-31446-6.

While many genetic diseases have effective treatments, they frequently progress rapidly to severe morbidity or mortality if those treatments are not implemented immediately. Since front-line physicians frequently lack familiarity with these diseases, timely molecular diagnosis may not improve outcomes. Herein we describe Genome-to-Treatment, an automated, virtual system for genetic disease diagnosis and acute management guidance. Diagnosis is achieved in 13.5 h by expedited whole genome sequencing, with superior analytic performance for structural and copy number variants. An expert panel adjudicated the indications, contraindications, efficacy, and evidence-of-efficacy of 9911 drug, device, dietary, and surgical interventions for 563 severe, childhood, genetic diseases. The 421 (75%) diseases and 1527 (15%) effective interventions retained are integrated with 13 genetic disease information resources and appended to diagnostic reports (https://gtrx.radygenomiclab.com). This system provided correct diagnoses in four retrospectively and two prospectively tested infants. The Genome-to-Treatment system facilitates optimal outcomes in children with rapidly progressive genetic diseases.

PMID:35882841 | DOI:10.1038/s41467-022-31446-6

Knowledge Generation

In Line Title

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Read more about this groundbreaking work.

Robert Wechler-Reva

PHD, Neuro-Oncology Program Director

Noted scientist Robert Wechsler-Reya, PhD, is also a professor and researcher at the Sanford Burnham Prebys Medical Discovery Institute (SBP) where he is focused on investigating the genes and nervous system signaling pathways that contribute to medulloblastoma, the most common malignant brain tumor in children.

News Features

October 22, 2020

Variety.com

Inside Our Child’s Battle With Mitochondrial Disease

“Despite a beautiful pregnancy and delivery with every prenatal screening and precaution taken, Evan was born with mitochondrial disease.” Lindzi Scharf shares a … Read More

October 14, 2020

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Lorem ipsum dolor sit amet, consectetur adipiscing elit. Praesent lobortis, est eget hendrerit rutrum, … Read More

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