Complex patterns of inheritance, including synergistic heterozygosity, in inborn errors of metabolism: Implications for precision medicine driven diagnosis and treatment

Vockley, Jerry; Dobrowolski, Steven F.; Arnold, Georgianne L.; Guerrero, Rubén Bonilla; Derks, Terry G J; Weinstein, David A.

doi:10.1016/j.ymgme.2019.07.011

Cited by 17 publications

(10 citation statements)

References 63 publications

(69 reference statements)

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“…In fact, the existence of a multigenic inheritance pattern in which pathogenic variants in multiple genes in a metabolic pathway lead to sufficient disruption of flux through the pathway, mimicking a monogenic disorder caused by homozygous defects in one gene in that pathway, has already been realized for a number of inherited metabolic disorders. In addition, widespread adoption of WES and WGS in medical genetics has led to the realization that individual patients with apparently hybrid phenotypes can have mutations in more than one gene, leading to a mixed genetic disorder [56]. It has long been known that even diseases caused by single-gene pathogenic variants can display substantial phenotypic variability, which may be due to genetic, environmental, or epigenetic modifiers.…”

Section: Discussionmentioning

confidence: 99%

Assessing Lysosomal Disorders in the NGS Era: Identification of Novel Rare Variants

Encarnação

Coutinho

Silva

et al. 2020

IJMS

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Lysosomal storage diseases (LSDs) are a heterogeneous group of genetic disorders with variable degrees of severity and a broad phenotypic spectrum, which may overlap with a number of other conditions. While individually rare, as a group LSDs affect a significant number of patients, placing an important burden on affected individuals and their families but also on national health care systems worldwide. Here, we present our results on the use of an in-house customized next-generation sequencing (NGS) panel of genes related to lysosome function as a first-line molecular test for the diagnosis of LSDs. Ultimately, our goal is to provide a fast and effective tool to screen for virtually all LSDs in a single run, thus contributing to decrease the diagnostic odyssey, accelerating the time to diagnosis. Our study enrolled a group of 23 patients with variable degrees of clinical and/or biochemical suspicion of LSD. Briefly, NGS analysis data workflow, followed by segregation analysis allowed the characterization of approximately 41% of the analyzed patients and the identification of 10 different pathogenic variants, underlying nine LSDs. Importantly, four of those variants were novel, and, when applicable, their effect over protein structure was evaluated through in silico analysis. One of the novel pathogenic variants was identified in the GM2A gene, which is associated with an ultra-rare (or misdiagnosed) LSD, the AB variant of GM2 Gangliosidosis. Overall, this case series highlights not only the major advantages of NGS-based diagnostic approaches but also, to some extent, its limitations ultimately promoting a reflection on the role of targeted panels as a primary tool for the prompt characterization of LSD patients.

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Section: Discussionmentioning

confidence: 99%

Assessing Lysosomal Disorders in the NGS Era: Identification of Novel Rare Variants

Encarnação

Coutinho

Silva

et al. 2020

IJMS

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“…For example, the relative lack of haem caused by the increased demand for cytochrome enzyme synthesis will activate ALAS transcription; moreover, excessive haem directly reduces ALAS1 mRNA stability and inhibits ALAS1 mRNA transcription. The balance between ALAS1 transcription and the haem content ensures that the transcription of ALAS1 maintains a low baseline activation state to prevent potential damage caused by excessive free haem and haem precursor accumulation [ 12 , 13 ].…”

Section: Introductionmentioning

confidence: 99%

“…The expression level of this heterodimer is positively correlated with the ALAS1 mRNA expression level in mice, suggesting that FOXO1 participates in the induction of ALAS1 transcription regulation in the form of a FOXO1/PGC-1 α heterodimer [ 14 , 17 ]. The human ALAS1 gene promoter region also contains a similar domain with the potential capability to bind the FOXO1/PGC-1 α heterodimer, although the mechanism is unclear [ 13 , 15 , 18 – 20 ]. However, researchers have not yet clearly determined whether and how FOXO1 transforms the stimulation of antituberculosis drugs into ALAS1 gene expression.…”

Section: Introductionmentioning

confidence: 99%

Genetic and Functional Evaluation of the Role of FOXO1 in Antituberculosis Drug-Induced Hepatotoxicity

Zhang

Jiao

Song

et al. 2021

Evidence-Based Complementary and Alternative Medicine

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Background. The accumulation of the hepatotoxic substance protoporphyrin IX (PPIX) induced by aminolevulinate synthase 1 (ALAS1) activation is one of the important mechanisms of antituberculosis drug-induced hepatotoxicity (ATDH). Forkhead box protein O1 (FOXO1) may activate ALAS1 transcription. However, little is known about their roles in ATDH; we performed a study to determine the association between polymorphisms in the two genes and ATDH susceptibility. Then, we verified this possible association by cellular functional experiments. Materials and Methods. Tag single-nucleotide polymorphisms (TagSNPs) in the two genes were genotyped in 746 tuberculosis patients. The frequencies of the alleles, genotypes, genetic models, and haplotype distribution of the variants were compared between the case and control groups. L-02 cells and HepG2 cells were incubated with the indicated concentration of isoniazid (INH) and rifampicin (RIF) for the desired times, and then the expression levels of ALAS1 and FOXO1 mRNAs and proteins were detected. HepG2 cells were transiently transfected with FOXO1 siRNA to observe the effect of changes in the FOXO1 expression on the cell survival rate and ALAS1 expression. Results. The C allele at rs2755237 and the T allele at rs4435111 in the FOXO1 gene were associated with a decreased risk of ATDH. The expression of ALAS1 in both L-02 cells and HepG2 cells was increased by the coadministration of INH/RIF (600/200 μM) for 24 h. Although FOXO1 expression was reduced slightly by the same treatment, its content in the nucleus was significantly increased. However, the cell survival rate and ALAS1 expression level were not significantly altered by the downregulation of FOXO1 in HepG2 cells. Conclusions. Variants of the rs4435111 and rs2755237 loci in the FOXO1 gene were associated with susceptibility to ATDH. Coadministration of INH/RIF promoted the transfer of FOXO1 from the cytoplasm to the nucleus, but the functional significance of its nuclear translocation requires further verification.

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“…Implicated organisms include influenza, parainfluenza, herpes, enteroviruses, coxsackie, rotavirus and mycoplasma among others [ [8] , [9] , [10] ]. Distinctive pathologic lesions on magnetic resonance imaging (MRI) are bilateral symmetrical signal abnormalities in thalami, brainstem, temporal lobe, limbic system, external capsule and occasionally basal ganglia; these lesions may undergo hemorrhagic conversion [ [2] , [3] , 5 , 6 , 8 , 10 , [13] , [14] , 15 ]. ANE1 follows an autosomal dominant Mendelian inheritance pattern but with incomplete penetrance [ [10] , [11] , [12] ], which could contribute to underdiagnosis.…”

Section: Introductionmentioning

confidence: 99%

RANBP2 susceptibility to infection-induced encephalopathy: Clinicoradiologic and molecular description in a Malaysian family

Chew

Ngu

2020

Molecular Genetics and Metabolism Reports

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Pathogenic variants in RANBP2 cause autosomal dominant familial and recurrent Acute Necrotizing Encephalopathy of Childhood (ANEC). Affected children typically experience a 3-stage disease: a 3 to 5 days prodrome of non-specific febrile illness, acute encephalopathy, and recovery with or without neurological sequelae or death. Neuroradiological finding of bilateral symmetrical thalamic lesions raise the suspicion of this diagnosis. A devastating disease, reported mortality approaches 1/3 of those affected and only approximately 10% of patients recover completely without sequelae. We report a Malaysian family with RANBP2 pathogenic variant c.1754C>T (p.Thr585Met). The clinical presentation and course over a maximum of 7 years, as well as neuroradiological features of the 3 affected children are described. In contrast to the reported high mortality and morbidity, our patients have recovered with minor sequelae. We would like to highlight the absence of pathogenic variants in both parents' blood, raising the possibility of germline mosaicism in one of the parents as the underlying genetic mechanism of inheritance. To our knowledge, this is the first report of germline mosaicism in RANBP2 Susceptibility to Infection-induced Encephalopathy.

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Complex patterns of inheritance, including synergistic heterozygosity, in inborn errors of metabolism: Implications for precision medicine driven diagnosis and treatment

Cited by 17 publications

References 63 publications

Assessing Lysosomal Disorders in the NGS Era: Identification of Novel Rare Variants

Assessing Lysosomal Disorders in the NGS Era: Identification of Novel Rare Variants

Genetic and Functional Evaluation of the Role of FOXO1 in Antituberculosis Drug-Induced Hepatotoxicity

RANBP2 susceptibility to infection-induced encephalopathy: Clinicoradiologic and molecular description in a Malaysian family

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