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

J Pediatr. 2021 Sep 8:S0022-3476(21)00877-5. doi: 10.1016/j.jpeds.2021.09.005. Online ahead of print.

ABSTRACT

OBJECTIVES: To assess associations between maternal smoking and congenital heart defects (CHDs) in offspring.

STUDY DESIGN: We performed a retrospective case-control study using data for cases of CHD (n=8,339) and non-malformed controls (n=11,020) children from all years (1997-2011) of the National Birth Defects Prevention Study. Maternal self-reported smoking one month before through three months after conception was evaluated as a binary (none, any) and categorical (light, medium, heavy) exposure. Multivariable logistic regression was used to estimate adjusted odds ratios (aOR) and 95% confidence intervals. Stratified analyses were performed for septal defects according to maternal age, pre-pregnancy body mass index, and maternal race/ethnicity.

RESULTS: Multiple CHDs displayed modest associations with any level of maternal periconceptional smoking independent of potential confounders; the strongest associations were for aggregated septal defects (OR 1.5 [1.3-1.7]), tricuspid atresia (OR 1.7 [1.0-2.7]), and double outlet right ventricle (DORV) (1.5 [1.1-2.1]). TA and DORV also displayed dose-response relationships. Among heavy smokers, the highest odds were again observed for TA (aOR 3.0 [1.5-6.1]) and DORV (aOR 1.5 [1.1-2.2]). Heavy smokers ≥35 years old more frequently had a child with a septal defect when compared with similarly aged non-smokers (aOR 2.3 [1.4-3.9]).

CONCLUSIONS: Maternal periconceptional smoking is most strongly associated with septal defects, TA and DORV; the risk for septal defects is modified by maternal age.

PMID:34508749 | DOI:10.1016/j.jpeds.2021.09.005

Child Neurol Open. 2021 Aug 5;8:2329048X211030723. doi: 10.1177/2329048X211030723. eCollection 2021 Jan-Dec.

ABSTRACT

We present a case of a young child with a rare metabolic disorder whose clinical presentation resembled that of autoimmune myasthenia gravis. The differential diagnosis was expanded when autoantibody testing was negative and the patient did not respond to standard immunomodulatory therapies. Rapid whole genome sequencing identified 2 rare variants of uncertain significance in the SLC52A3 gene shown to be in compound heterozygous state after parental testing. Biallelic mutations in SLC52A3 are associated with Riboflavin Transporter Deficiency, which in its untreated form, results in progressive neurodegeneration and death. Supplementation with oral riboflavin has been shown to limit disease progression and improve symptoms in some patients. When the diagnosis is suspected, patients should be started on supplementation immediately while awaiting results from genetic studies.

PMID:34395718 | PMC:PMC8361551 | DOI:10.1177/2329048X211030723

Am J Med Genet A. 2021 Aug 5. doi: 10.1002/ajmg.a.62439. Online ahead of print.

ABSTRACT

Bladder exstrophy (BE) is a rare, lower ventral midline defect with the bladder and part of the urethra exposed. The etiology of BE is unknown but thought to be influenced by genetic variation with more recent studies suggesting a role for rare variants. As such, we conducted paired-end exome sequencing in 26 child/mother/father trios. Three children had rare (allele frequency ≤ 0.0001 in several public databases) inherited variants in TSPAN4, one with a loss-of-function variant and two with missense variants. Two children had loss-of-function variants in TUBE1. Four children had rare missense or nonsense variants (one per child) in WNT3, CRKL, MYH9, or LZTR1, genes previously associated with BE. We detected 17 de novo missense variants in 13 children and three de novo loss-of-function variants (AKR1C2, PRRX1, PPM1D) in three children (one per child). We also detected rare compound heterozygous loss-of-function variants in PLCH2 and CLEC4M and rare inherited missense or loss-of-function variants in additional genes applying autosomal recessive (three genes) and X-linked recessive inheritance models (13 genes). Variants in two genes identified may implicate disruption in cell migration (TUBE1) and adhesion (TSPAN4) processes, mechanisms proposed for BE, and provide additional evidence for rare variants in the development of this defect.

PMID:34355505 | DOI:10.1002/ajmg.a.62439

Open Forum Infect Dis. 2021 Jul 17;8(7):ofab346. doi: 10.1093/ofid/ofab346. eCollection 2021 Jul.

ABSTRACT

BACKGROUND: Osteoarticular infections (OAIs) are frequently encountered in children. Treatment may be guided by isolation of a pathogen; however, operative cultures are often negative. Metagenomic next-generation sequencing (mNGS) allows for broad and sensitive pathogen detection that is culture-independent. We sought to evaluate the diagnostic utility of mNGS in comparison to culture and usual care testing to detect pathogens in acute osteomyelitis and/or septic arthritis in children.

METHODS: This was a single-site study to evaluate the use of mNGS in comparison to culture to detect pathogens in acute pediatric osteomyelitis and/or septic arthritis. Subjects admitted to a tertiary children’s hospital with suspected OAI were eligible for enrollment. We excluded subjects with bone or joint surgery within 30 days of admission or with chronic osteomyelitis. Operative samples were obtained at the surgeon’s discretion per standard care (fluid or tissue) and based on imaging and operative findings. We compared mNGS to culture and usual care testing (culture and polymerase chain reaction [PCR]) from the same site.

RESULTS: We recruited 42 subjects over the enrollment period. mNGS of the operative samples identified a pathogen in 26 subjects compared to 19 subjects in whom culture identified a pathogen. In 4 subjects, mNGS identified a pathogen where combined usual care testing (culture and PCR) was negative. Positive predictive agreement and negative predictive agreement both were 93.0% for mNGS.

CONCLUSIONS: In this single-site prospective study of pediatric OAI, we demonstrated the diagnostic utility of mNGS testing in comparison to culture and usual care (culture and PCR) from operative specimens.

PMID:34322569 | PMC:PMC8314938 | DOI:10.1093/ofid/ofab346

Mol Genet Genomic Med. 2021 Jun 2:e1623. doi: 10.1002/mgg3.1623. Online ahead of print.

ABSTRACT

BACKGROUND: Cockayne syndrome (CS) is a rare autosomal recessive disorder characterized by growth failure and multisystemic degeneration. Excision repair cross-complementation group 6 (ERCC6 OMIM: *609413) is the gene most frequently mutated in CS.

METHODS: A child with pre and postnatal growth failure and progressive neurologic deterioration with multisystem involvement, and with nondiagnostic whole-exome sequencing, was screened for causal variants with whole-genome sequencing (WGS).

RESULTS: WGS identified biallelic ERCC6 variants, including a previously unreported intronic variant. Pathogenicity of these variants was established by demonstrating reduced levels of ERCC6 mRNA and protein expression, normal unscheduled DNA synthesis, and impaired recovery of RNA synthesis in patient fibroblasts following UV-irradiation.

CONCLUSION: The study confirms the pathogenicity of a previously undescribed upstream intronic variant, highlighting the power of genome sequencing to identify noncoding variants. In addition, this report provides evidence for the utility of a combination approach of genome sequencing plus functional studies to provide diagnosis in a child for whom a lengthy diagnostic odyssey, including exome sequencing, was previously unrevealing.

PMID:34076366 | DOI:10.1002/mgg3.1623

Knowledge Generation

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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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