Publications by authors named "Julie A Neidich"

4 Publications

  • Page 1 of 1

Diagnostic Utility of Next-Generation Sequencing for Disorders of Somatic Mosaicism: A Five-Year Cumulative Cohort.

Am J Hum Genet 2019 10;105(4):734-746

Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO 63110, USA; Department of Genetics, Washington University School of Medicine, Saint Louis, MO 63110, USA. Electronic address:

Disorders of somatic mosaicism (DoSM) are a diverse group of syndromic and non-syndromic conditions caused by mosaic variants in genes that regulate cell survival and proliferation. Despite overlap in gene space and technical requirements, few clinical labs specialize in DoSM compared to oncology. We adapted a high-sensitivity next-generation sequencing cancer assay for DoSM in 2014. Some 343 individuals have been tested over the past 5 years, 58% of which had pathogenic and likely pathogenic (P/LP) findings, for a total of 206 P/LP variants in 22 genes. Parameters associated with the high diagnostic yield were: (1) deep sequencing (∼2,000× coverage), (2) a broad gene set, and (3) testing affected tissues. Fresh and formalin-fixed paraffin embedded tissues performed equivalently for identification of P/LP variants (62% and 71% of individuals, respectively). Comparing cultured fibroblasts to skin biopsies suggested that culturing might boost the allelic fraction of variants that confer a growth advantage, specifically gain-of-function variants in PIK3CA. Buccal swabs showed high diagnostic sensitivity in case subjects where disease phenotypes manifested in the head or brain. Peripheral blood was useful as an unaffected comparator tissue to determine somatic versus constitutional origin but had poor diagnostic sensitivity. Descriptions of all tested individuals, specimens, and P/LP variants included in this cohort are available to further the study of the DoSM population.
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http://dx.doi.org/10.1016/j.ajhg.2019.09.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6817554PMC
October 2019

Outcome of infants diagnosed with 3-methyl-crotonyl-CoA-carboxylase deficiency by newborn screening.

Mol Genet Metab 2012 Aug 20;106(4):439-41. Epub 2012 Apr 20.

Department of Pediatrics, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.

Introduction: 3-Methyl CoA carboxylase (3-MCC) deficiency is an inborn error of metabolism in the catabolism of the amino acid leucine. Original reports suggested this disorder was associated with significant neurological and biochemical effects. However newborn screening has identified a higher than expected incidence of this disorder with apparent normal outcome in most cases.

Method: A retrospective analysis of thirty-five cases of 3-MCC deficiency identified by newborn screening and diagnosed by enzyme or molecular analysis.

Results: There was a strong inverse correlation between initial C5OH level and residual enzyme activity. A few reports of hypoglycemia, ketosis, poor feeding/failure to thrive or fasting intolerance were reported, but there was no clear relationship between symptoms and residual enzyme activity. Developmental outcome included several children with mental retardation (including one with Down syndrome and one with schizencephaly) and two with Autism Spectrum disorders but there was no apparent relationship to residual enzyme activity. Free carnitine deficiency was relatively common.

Discussion: Although residual enzyme activity was clearly related to metabolite elevation, there was no apparent relationship with other measures of outcome. The number of reports of neurologic abnormalities or metabolic symptoms (poor feeding, hypoglycemia, fasting intolerance, etc.) is concerning, but the significance is unclear in this retrospective sample.
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http://dx.doi.org/10.1016/j.ymgme.2012.04.006DOI Listing
August 2012

Asymptomatic maternal combined homocystinuria and methylmalonic aciduria (cblC) detected through low carnitine levels on newborn screening.

J Pediatr 2009 Dec;155(6):924-7

Division of Medical Genetics, Harbor-UCLA Medical Center, Torrance, CA 90502, USA.

A symptom-free woman gave birth to a girl with a low carnitine level on newborn screening. The baby was unaffected, but the mother had biochemical abnormalities and mutations characteristic of the cblC defect of vitamin B(12) metabolism (late-onset form). This patient with cblC was detected through her infant's newborn screening.
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http://dx.doi.org/10.1016/j.jpeds.2009.06.046DOI Listing
December 2009

Improving accuracy of Tay Sachs carrier screening of the non-Jewish population: analysis of 34 carriers and six late-onset patients with HEXA enzyme and DNA sequence analysis.

Pediatr Res 2010 Feb;67(2):217-20

Molecular Genetics Department, Quest Diagnostics Nichols Institute, San Juan Capistrano, California 92690, USA.

The purpose of this study was to determine whether combining different testing modalities namely beta-hexosaminidase A (HEXA) enzyme analysis, HEXA DNA common mutation assay, and HEXA gene sequencing could improve the sensitivity for carrier detection in non-Ashkenazi (AJ) individuals. We performed a HEXA gene sequencing assay, a HEXA DNA common mutation assay, and a HEXA enzyme assay on 34 self-reported Tay-Sachs disease (TSD) carriers, six late-onset patients with TSD, and one pseudodeficiency allele carrier. Sensitivity of TSD carrier detection was 91% for gene sequencing compared with 91% for the enzyme assay and 52% for the DNA mutation assay. Gene sequencing combined with enzyme testing had the highest sensitivity (100%) for carrier detection. Gene sequencing detected four novel mutations, three of which are predicted to be disease causing [118.delT, 965A-->T (D322V), and 775A-->G (T259A)]. Gene sequencing is useful in identifying rare mutations in patients with TSD and their families, in evaluating spouses of known carriers for TSD who have indeterminate enzyme analysis and negative for common mutation analysis, and in resolving ambiguous enzyme testing results.
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http://dx.doi.org/10.1203/PDR.0b013e3181c6e318DOI Listing
February 2010