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Clinical Manifestation of Mitochondrial Disorders in Childhood
Published in Shamim I. Ahmad, Handbook of Mitochondrial Dysfunction, 2019
The most frequent cardiac manifestation is cardiomyopathy with minimal occurence of 20–30% of children with mitochondrial disorder (Yaplito-Lee et al., 2007). This frequency varies over age, being more frequent in neonatal and paediatric patients (40% out of 120 neonates in the study of Honzik et al., 2012, 58% in 113 children in the study of Scaglia et al., 2004) than in adults with various mtDNA or nDNA mutations (cardiac involvement in 30% out of 260 patients in the study of Wahbi et al., 2015). The most common is a hypertrophic cardiomyopathy (Lev et al., 2004; Yaplito-Lee et al., 2007; Bates et al., 2012), when up to 60% of patients can manifest with this particular cardiomyopathy form (Scaglia et al., 2004). Other cardiomyopathies include dilated, restrictive, histiocytoid or unclassified cardiomyopathy, or Takotsubo syndrome (Finsterer and Kothari, 2014). The differential diagnosis of cardiomyopathy as a hallmark of the disease is very broad includes TMEM70, Barth syndrome, Sengers syndrome, SCO2, AARS2, AIFM, TK2, DNAJC19, and many others.
Targeted panel sequencing identifies a novel NR2F1 mutations in a patient with Bosch–Boonstra–Schaaf optic atrophy syndrome
Published in Ophthalmic Genetics, 2019
Sung Eun Park, Jihei Sara Lee, Seung-Tae Lee, Hye Young Kim, Sueng-Han Han, Jinu Han
DNA of the proband was captured with custom-targeted sequencing panel (Celemics, Seoul, Korea) and sequenced on Illumina NextSeq550 (Illumina Inc, San Diego, USA). Our customized-targeted panel included 429 genes associated with various ophthalmic disorders including hereditary optic neuropathy (OPA1, OPA3, MFN2, WFS1, RTN4IP1, SLC25A46, TMEM126A, UCHL1, ACO2, NBAS, NR2F1, YME1L1, NDUFS1, DNAJC19, CISD2, FXN, AUH, C12orf65, POLG, SPG7, AFG3L2, C19orf12, TIMM8A). Briefly, raw sequence data were mapped to GRCh37 (hg19) using the Burrow-Wheeler Aligner algorithm, followed by removal of duplicate reads, base quality recalibration, and variant calling using the Genome Analysis Toolkit v3.8 as described previously (3). Targeted next-generation sequencing revealed a novel heterozygous NR2F1 c.513C>G;p.Tyr171Ter nonsense variant, and this variant was absent from various population genomic databases (1000 Genome Project, Exome Variant Server, Exome Aggregation Consortium or Genome Aggregation Database, accessed in September 2018). The c.513C>G variant was predicted to be deleterious by in silico prediction programs (Combined Annotation Dependent Depletion, CADD:37, Functional Analysis through Hidden Markov Model, FATHMM:0.9857). This variant was considered ‘likely pathogenic’ according to the guideline of American College of Medical Genetics and Association for Molecular Pathology (4). This c.513C>G variant is located between DNA-binding domain and ligand-binding domain of NR2F1 (Figure 2b). The parental testing could not be performed.
Novel missense WFS1 variant causing autosomal dominant atypical Wolfram syndrome
Published in Ophthalmic Genetics, 2022
Hailey Mair, Nicholas Fowler, Maria E. Papatzanaki, Padmaja Sudhakar, Ramiro S. Maldonado
The proband (Case 1) was initially evaluated by referring providers for subnormal vision and mild optic atrophy. Initial investigation included fundus autofluorescence (Optos California, Marlborough, MA, USA), optical coherence tomography (Spectralis, Heidelberg Engineering, Heidelberg, Germany), static perimetry (Humphrey visual field analyzer 3, Zeiss), Pelli-Robson testing, Ishihara plate testing and Titmus stereoacuity. Once optic atrophy was confirmed, a metabolic and paraneoplastic testing performed included: Neuromyelitis optica NMP/Aquaporin-4 and Myelin Oligondendrocyte Glycoprotein MOG serum antibodies; heavy metals screen in urine and blood including arsenic, mercury, and lead; Vitamins B1, B12, and folate serum levels, methylmalonic acid, erythrocyte sedimentation rate, C-reactive protein, RPR, ANA, ACE, and Quantiferon Gold; ANNA-1,2,3, AGNA-1, PCA-1,2,TRAMphiphysin Ab, CRMP-5, striational Ab, P/Q type calcium channel Ab, N-type calcium channel Ab, Ach receptor (muscle) binding Ab, Neuronal K+ channel Ab. Next-generation sequencing of OPA1, OPA3, and LHON was also performed. Further genetic testing included the Blueprint Genetics Optic Atrophy panel (version 4, 19 October 2019) Plus Analysis. This analysis included 31 genes (ACO2, AFG3L2, ATAD3A, AUH, C12ORF65, C19ORF12, CISD2, DNAJC19, DNM1L, FDXR, MECR, MFN2, MTPAP, NDUFS1, NR2F1, OPA1, OPA3, POLG, PRPS1, RTN4IP1, SLC25A46, SLC52A2, SNX10, SPG7, TIMM8A, TMEM126A, TSFM, UCHL1, WFS1, YME1L1, and ZNHIT3.) The proband’s mother (Case 2) was examined at Iassis Medical Center (Chania-Greece). Examination included fundus autofluorescence, optical coherence tomography, automated perimetry, and next-generation sequencing of the WFS1 gene.