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Background Methods to call, analyze and visualize copy number variations (CNVs) from massive parallel sequencing data have been widely adopted in clinical practice and genetic research. To enable a streamlined analysis of CNV data, comprehensive annotations and good visualizations are indispensable. The ability to detect single exon CNVs is another important feature for genetic testing. Nonetheless, most available open-source tools come with limitations in at least one of these areas. One additional drawback is that available tools deliver data in an unstructured and static format which requires subsequent visualization and formatting efforts. Results Here we present CNVizard, an interactive Streamlit app allowing a comprehensive visualization of CNVkit data. Furthermore, combining CNVizard with the CNVand pipeline allows the annotation and visualization of CNV or SV VCF files from any CNV caller. Conclusion CNVizard, in combination with CNVand, enables the comprehensive and streamlined analysis of short- and long-read sequencing data and provide an intuitive webapp-like experience enabling an interactive visualization of CNV data.

Background Heterozygous mutations of the hydroxymethylbilane synthase gene can lead to acute intermittent porphyria, with episodic abdominal pain and neuropsychiatric symptoms. The heme precursors 5-aminolevulinic acid and porphobilinogen accumulate due to enzyme deficiency. Case reports of biallelic pathogenic hydroxymethylbilane synthase gene variants are very rare. Methods This case report presents a severely affected boy with biallelic pathogenic hydroxymethylbilane synthase gene variants and includes literature overview of other case reports and experimental data. Case presentation At the age of 2 years, a Caucasian boy with pathologic psychomotor development was diagnosed with biallelic pathogenic hydroxymethylbilane synthase gene variants. As in previous case reports, he did not exhibit symptoms of acute intermittent porphyria, but progressive cystic leukoencephalopathy and neurological decay. In his urine, 5-aminolevulinic acid and porphobilinogen were markedly elevated, but in cerebrospinal fluid just porphobilinogen. Literature review Data of human and animal studies indicate that neurologic symptoms of acute intermittent porphyria are caused by 5-aminolevulinic acid, which episodically accumulates from hepatic origin. Here, as long-term treatment, the inhibition of hepatic heme synthesis with the small interfering RNA givosiran has proven to be effective. In case of biallelic pathogenic hydroxymethylbilane synthase gene variants, the heme precursors 5-aminolevulinic acid or porphobilinogen originating from the liver or central nervous system could be causative, and absolute heme deficiency in the central nervous system is another hypothesis. However, parenterally administered heme, which is effective in acute intermittent porphyria, does not reach the central nervous system. In one case of biallelic pathogenic hydroxymethylbilane synthase gene variants, a liver transplantation did not lead to long-term benefit. Conclusion For differential diagnosis of cystic leukoencephalopathy, biallelic pathogenic hydroxymethylbilane synthase gene variants should be considered. Its pathogenesis probably differentiates from acute intermittent porphyria. To date, there is no promising therapeutic approach.

Macrodomains are conserved protein folds associated with ADP-ribose binding and turnover. ADP-ribosylation is a posttranslational modification catalyzed primarily by ARTD (aka PARP) enzymes in cells. ARTDs transfer either single or multiple ADP-ribose units to substrates, resulting in mono- or poly-ADP-ribosylation. TARG1/C6orf130 is a macrodomain protein that hydrolyzes mono-ADP-ribosylation and interacts with poly-ADP-ribose chains. Interactome analyses revealed that TARG1 binds strongly to ribosomes and proteins associated with rRNA processing and ribosomal assembly factors. TARG1 localized to transcriptionally active nucleoli, which occurred independently of ADP-ribose binding. TARG1 shuttled continuously between nucleoli and nucleoplasm. In response to DNA damage, which activates ARTD1/2 (PARP1/2) and promotes synthesis of poly-ADP-ribose chains, TARG1 re-localized to the nucleoplasm. This was dependent on the ability of TARG1 to bind to poly-ADP-ribose. These findings are consistent with the observed ability of TARG1 to competitively interact with RNA and PAR chains. We propose a nucleolar role of TARG1 in ribosome assembly or quality control that is stalled when TARG1 is re-located to sites of DNA damage.

BackgroundThe chromosomal region 11p15.5 harbours two imprinting centres (H19/IGF2:IG-DMR/IC1, KCNQ1OT1:TSS-DMR/IC2). Molecular alterations of the IC2 are associated with Beckwith-Wiedemann syndrome (BWS), whereas only single patients with growth retardation and Silver-Russell syndrome (SRS) features have been reported. CNVs in 11p15.5 account for less than 1% of patients with BWS and SRS, and they mainly consist of duplications of both ICs either affecting the maternal (SRS) or the paternal (BWS) allele. However, this correlation does not apply to smaller CNVs, which are associated with diverse clinical outcomes.Methods and resultsWe identified a family with a 132 bp deletion within the KCNQ1OT1 gene, associated with growth retardation in case of paternal transmission but a normal phenotype when maternally inherited. Comparison of molecular and clinical data with cases from the literature helped to delineate its functional relevance.ConclusionMicrodeletions within the paternal IC2 affecting the KCNQ1OT1 gene have been described in only five families, and they all include the differentially methylated region KCNQ1OT1:TSS-DMR/IC2 and parts of the KCNQ1 gene. However, these deletions have different impacts on the expression of both genes and the cell-cycle inhibitor CDKN1C. They thereby cause different phenotypes. The 132 bp deletion is the smallest deletion in the IC2 reported so far. It does not affect the IC2 methylation in general and the coding sequence of the KCNQ1 gene. Thus, the deletion is only associated with a growth retardation phenotype when paternally transmitted but not with other clinical features in case of maternal inheritance as observed for larger deletions.

Homozygous VPS50 variants have been previously described in two unrelated patients with a neurodevelopmental disorder with microcephaly, seizures and neonatal cholestasis. VPS50 encodes a subunit that is unique to the heterotetrameric endosome-associated recycling protein (EARP) complex. The other subunits of the EARP complex, such as VPS51, VPS52 and VPS53, are also shared by the Golgi-associated retrograde protein complex. We report on an 18-month-old female patient with biallelic VPS50 variants. She carried a paternally inherited heterozygous nonsense c.13A>T; p.(Lys5*) variant. By long-read genome sequencing, we characterised a structural variant with a 4.3 Mb inversion flanked by deletions at both breakpoints on the maternal allele. The ~428 kb deletion at the telomeric inversion breakpoint encompasses the entire VPS50 gene. We demonstrated a deficiency of VPS50 in patient-derived fibroblasts, confirming the loss-of-function nature of both VPS50 variants. VPS53 and VPS52 protein levels were significantly reduced and absent, respectively, in fibroblasts of the patient. These data show that VPS50 and/or EARP deficiency and the associated functional defects underlie the phenotype in patients with VPS50 pathogenic variants. The VPS50-related core phenotype comprises severe developmental delay, postnatal microcephaly, hypoplastic corpus callosum, neonatal low gamma-glutamyl transpeptidase cholestasis and failure to thrive. The disease is potentially fatal in early childhood.

Deciphering the function of the many genes previously classified as uncharacterized \"open reading frame\" (orf) completes our understanding of cell function and its pathophysiology. Whole-exome sequencing, yeast 2-hybrid and transcriptome analyses together with molecular characterization are used here to uncover the function of the C2orf69 gene. We identified loss-of-function mutations in the uncharacterized C2orf69 gene in eight individuals with brain abnormalities involving hypomyelination and microcephaly, liver dysfunction and recurrent autoinflammation. C2orf69 contains an N-terminal signal peptide that is required and sufficient for mitochondrial localization. Consistent with mitochondrial dysfunction, patients showed signs of respiratory chain defect and a CRISPR-Cas9 knockout cell model of C2orf69 had similar respiratory chain defects. Patient-derived cells revealed alterations in immunological signaling pathways. Deposits of PAS-positive material in tissues from affected individuals together with decreased glycogen branching enzyme 1 (GBE1) activity indicated an additional impact of C2orf69 on glycogen metabolism. Our study identifies C2orf69 as an important regulator of human mitochondrial function and suggests an additional influence on other metabolic pathways.

BACKGROUND. Deciphering the function of the many genes previously classified as uncharacterized open reading frame (ORF) would complete our understanding of a cell's function and its pathophysiology. METHODS. Whole-exome sequencing, yeast 2-hybrid and transcriptome analyses, and molecular characterization were performed in this study to uncover the function of the C2orf69 gene. RESULTS. We identified loss-of-function mutations in the uncharacterized C2orf69 gene in 8 individuals with brain abnormalities involving hypomyelination and microcephaly, liver dysfunction, and recurrent autoinflammation. C2orf69 contains an N-terminal signal peptide that is required and sufficient for mitochondrial localization. Consistent with mitochondrial dysfunction, the patients showed signs of respiratory chain defects, and a CRISPR/Cas9-KO cell model of C2orf69 had similar respiratory chain defects. Patient-derived cells revealed alterations in immunological signaling pathways. Deposits of periodic acid-Schiff-positive (PAS-positive) material in tissues from affected individuals, together with decreased glycogen branching enzyme 1 (GBE1) activity, indicated an additional impact of C2orf69 on glycogen metabolism. CONCLUSIONS. Our study identifies C2orf69 as an important regulator of human mitochondrial function and suggests that this gene has additional influence on other metabolic pathways.

Methods to call, analyze and visualize copy number variations (CNVs) from massive parallel sequencing data have been widely adopted in clinical practice and genetic research. To enable a streamlined analysis of CNV data, comprehensive annotation and good visualization are indispensable. The ability to detect single exon CNVs is another important feature for genetic testing. Nonetheless, most available open-source tools come with limitations in at least one of these areas. One drawback is that available tools deliver data in an unstructured and static format which requires subsequent visualization and formatting efforts. Here we present CNVizard, a lightweight streamlit app which requires minimal computational knowledge, and which is compatible with widely used CNV processing tools (CNVkit and AnnotSV). CNVizard can process short- and long-read sequencing data and provides an intuitive webapp-like experience enabling an interactive visualization of CNV data.