Diagnosis of D-Bifunctional Protein Deficiency through Whole-Genome Sequencing: Implications for Cost-Effective Care

Khromykh, Alina; Solomon, Benjamin D.; Bodian, Dale L.; Leon, Eyby; Iyer, Ramaswamy K.; Baker, Robin; Ascher, David P.; Baveja, Rajiv; Vockley, Joseph G.; Niederhuber, John E.

doi:10.1159/000433621

Cited by 6 publications

(5 citation statements)

References 26 publications

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“…Since first described by Watkins et al in 1989, 5 there have been very few reports about DBP deficiency and its management. 1 6 7 8 9 10 11 12 Our patient was brought to the medical attention due to generalized hypotonia, clubfoot, and craniofacial dysmorphism at birth. Although chromosome microarray is considered a first-tier test for such symptoms, 13 metabolic work-up including serum VLCFAs must be included for distinguishing the inborn error metabolism which show a facial dysmorphism and neurologic progression.…”

Section: Discussionmentioning

confidence: 98%

“…Recent reports showed early diagnosis of children with DBP deficiency using clinical exome sequencing despite their ambiguous manifestations. 9 10 11 12 Genotypes including missense, nonsense, or deletion mutations and locations of exon could help predict the prognosis of the patient. 2 Our patient had missense mutations located in exons 6 and 12 and the DBP type III phenotype.…”

Section: Discussionmentioning

confidence: 99%

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First Case of Peroxisomal D-bifunctional Protein Deficiency with Novel HSD17B4 Mutations and Progressive Neuropathy in Korea

Bae

Lim

et al. 2020

J Korean Med Sci

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Peroxisomal D-bifunctional protein (DBP), encoded by the HSD17B4 gene, catalyzes β-oxidation of very long chain fatty acids (VLCFAs). The deficiency of this peroxisomal enzyme leads to the accumulation of VLCFAs, causing multisystemic manifestations including the brain, retina, adrenal gland, hearing, and skeletal system. Herein, we report the first Korean neonatal case of peroxisomal DBP deficiency and the clinical prognosis over 2 years. This patient showed craniofacial dysmorphism, club foot, and seizures with cyanosis one day after birth. Elevated VLCFAs levels were indicative of a peroxisomal disorder. Targeted exome sequencing was performed and two missense mutations p.Asp117Val and p.Phe279Ser in the HSD17B4 gene were identified. The patient had type III DBP deficiency; therefore, docosahexaenoic acid and non-soluble vitamins were administered. However, progressive nystagmus, optic nerve atrophy, and bilateral hearing defects were observed and follow-up brain imaging revealed leukodystrophy and brain atrophy. Multiple anti-epileptic drugs were required to control the seizures. Over two years, the patient achieved normal growth with home ventilation and tube feeding. Hereby, the subject's parents had support during the second pregnancy from the proven molecular information. Moreover, targeted exome sequencing is an effective diagnostic approach, considering genetic heterogeneity of Zellweger spectrum disorders.

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

First Case of Peroxisomal D-bifunctional Protein Deficiency with Novel HSD17B4 Mutations and Progressive Neuropathy in Korea

Bae

Lim

et al. 2020

J Korean Med Sci

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“…The 4,979,845 quality-filtered small variants and 5094 copy number variable segments in the trio were prioritized by allele frequency, inheritance pattern, associated phenotype, and proneness of genomic regions to sequencing artifacts using SAVANNA ( Supplemental Fig. S2 ; Bodian et al 2014 ; Stittrich et al 2014 ; Khromykh et al 2015 ), resulting in candidate variants in nine genes ( Table 1 ). Candidate de novo variants were identified in NEDD4L and GSK3A , homozygous variants in C14orf28 and EPCAM , potential compound heterozygous variants in DMRT1 , MTCL1 , and NEDD4L , and heterozygous variants possibly associated with dominant inheritance with incomplete penetrance in SCN5A and DTNA .…”

Section: Resultsmentioning

confidence: 99%

Genomic analysis of an infant with intractable diarrhea and dilated cardiomyopathy

Bodian

Vilboux

Hourigan

et al. 2017

Cold Spring Harb Mol Case Stud

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We describe a case of an infant presenting with intractable diarrhea who subsequently developed dilated cardiomyopathy, for whom a diagnosis was not initially achieved despite extensive clinical testing, including panel-based genetic testing. Research-based whole-genome sequences of the proband and both parents were analyzed by the SAVANNA pipeline, a variant prioritization strategy integrating features of variants, genes, and phenotypes, which was implemented using publicly available tools. Although the intestinal morphological abnormalities characteristic of congenital tufting enteropathy (CTE) were not observed in the initial clinical gastrointestinal tract biopsies of the proband, an intronic variant, EPCAM c.556-14A>G, previously identified as pathogenic for CTE, was found in the homozygous state. A newborn cousin of the proband also presenting with intractable diarrhea was found to carry the same homozygous EPCAM variant, and clinical testing revealed intestinal tufting and loss of EPCAM staining. This variant, however, was considered nonexplanatory for the proband's dilated cardiomyopathy, which could be a sequela of the child's condition and/or related to other genetic variants, which include de novo mutations in the genes NEDD4L and GSK3A and a maternally inherited SCN5A variant. This study illustrates three ways in which genomic sequencing can aid in the diagnosis of clinically challenging patients: differential diagnosis despite atypical clinical presentation, distinguishing the possibilities of a syndromic condition versus multiple conditions, and generating hypotheses for novel contributory genes.

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“…We have tested and benchmarked PDR with 27 patient cases from Inova Translational Medicine Institute, Fairfax, VA (ITMI). Some of these cases have been studied and published elsewhere in different contexts [ 34 – 40 ]. For the present analysis, fastq files were used to call variants within the BxWB hereditary disease pipeline [ 41 ] that directly exports data to Ingenuity Variant Analysis.…”

Section: Resultsmentioning

confidence: 99%

Leveraging network analytics to infer patient syndrome and identify causal genes in rare disease cases

Krämer¹,

Shah²,

Rebres³

et al. 2017

BMC Genomics

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BackgroundNext-generation sequencing is widely used to identify disease-causing variants in patients with rare genetic disorders. Identifying those variants from whole-genome or exome data can be both scientifically challenging and time consuming. A significant amount of time is spent on variant annotation, and interpretation. Fully or partly automated solutions are therefore needed to streamline and scale this process.ResultsWe describe Phenotype Driven Ranking (PDR), an algorithm integrated into Ingenuity Variant Analysis, that uses observed patient phenotypes to prioritize diseases and genes in order to expedite causal-variant discovery. Our method is based on a network of phenotype-disease-gene relationships derived from the QIAGEN Knowledge Base, which allows for efficient computational association of phenotypes to implicated diseases, and also enables scoring and ranking.ConclusionsWe have demonstrated the utility and performance of PDR by applying it to a number of clinical rare-disease cases, where the true causal gene was known beforehand. It is also shown that PDR compares favorably to a representative alternative tool.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-017-3910-4) contains supplementary material, which is available to authorized users.

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Diagnosis of D-Bifunctional Protein Deficiency through Whole-Genome Sequencing: Implications for Cost-Effective Care

Cited by 6 publications

References 26 publications

First Case of Peroxisomal D-bifunctional Protein Deficiency with Novel HSD17B4 Mutations and Progressive Neuropathy in Korea

First Case of Peroxisomal D-bifunctional Protein Deficiency with Novel HSD17B4 Mutations and Progressive Neuropathy in Korea

Genomic analysis of an infant with intractable diarrhea and dilated cardiomyopathy

Leveraging network analytics to infer patient syndrome and identify causal genes in rare disease cases

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