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The majority of heterotaxy cases do not obtain a molecular diagnosis, although pathogenic variants in more than 50 genes are known to cause heterotaxy. A heterozygous missense variant in DAND5 , a nodal inhibitor, which functions in early development for establishment of right-left patterning, has been implicated in heterotaxy. Recently, the first case was reported of a DAND5 biallelic loss-of-function (LoF) variant in an individual with heterotaxy. Here, we describe a second unrelated individual with heterotaxy syndrome and a homozygous frameshift variant in DAND5 (NM_152654.2:c.197del [p.Leu66ArgfsTer22]). Using an in vitro assay, we demonstrate that the DAND5 c.197del variant is unable to inhibit nodal signaling when compared with the wild-type expression construct. This work strengthens the genetic and functional evidence for biallelic LoF variants in DAND5 causing an autosomal recessive heterotaxy syndrome., (© 2022 Ganapathi et al.; Published by Cold Spring Harbor Laboratory Press.)

Vacuolar ATPases (V-ATPases) are large multisubunit proton pumps conserved among all eukaryotic cells that are involved in diverse functions including acidification of membrane-bound intracellular compartments. The ATP6AP1 gene encodes an accessory subunit of the vacuolar (V)-ATPase protein pump. Pathogenic variants in ATP6AP1 have been described in association with a congenital disorder of glycosylation (CDG), which are highly variable, but often characterized by immunodeficiency, hepatopathy, and neurologic manifestations. Although the most striking and common clinical feature is hepatopathy, the phenotypic and genotypic spectrum of ATP6AP1-CDG continues to expand. Here, we report identical twins who presented with acute liver failure and jaundice. Prenatal features included cystic hygroma, atrial septal defect, and ventriculomegaly. Postnatal features included pectus carinatum, connective tissue abnormalities, and hypospadias. Whole-exome sequencing (WES) revealed a novel de novo in-frame deletion in the ATP6AP1 gene (c.230_232delACT;p.Tyr77del). Although both twins have the commonly reported clinical feature of hepatopathy seen in other individuals with ATP6AP1-CDG -related disorder, they do not have neurological sequelae. This report expands the phenotypic spectrum of ATP6AP1-CDG- related disorder with both probands exhibiting unique prenatal and postnatal features, including fetal ventriculomegaly, umbilical hernia, pectus carinatum, micropenis, and hypospadias. Furthermore, this case affirms that neurological features described in the initial case series on ATP6AP1-CDG do not appear to be central, whereas the prenatal and connective tissue manifestations may be more common than previously thought. This emphasizes the importance of long-term clinical follow-up and variant interpretation using current updated recommendations., (© 2022 Barua et al.; Published by Cold Spring Harbor Laboratory Press.)

McArdle disease is a debilitating glycogen storage disease with typical onset in childhood. Here, we describe a former competitive athlete with early adult-onset McArdle disease and a septuagenarian with a history of exercise intolerance since adolescence who was evaluated for proximal muscle weakness. Exome sequencing identified biallelic variants in the PYGM gene for both cases. The former athlete has the common, well-known pathogenic variant p.(Arg50Ter) in trans with a novel missense variant, p.(Asp694Glu). The second individual has a previously described homozygous missense variant, p.(Arg771Gln). Here, we describe the clinical course, enzyme-testing results using muscle tissue, and molecular findings for the individuals and add to the knowledge of the genotypic spectrum of this disorder., (© 2022 Thomas-Wilson et al.; Published by Cold Spring Harbor Laboratory Press.)

Sclerosing epithelioid fibrosarcoma (SEF) is a rare and aggressive soft-tissue sarcoma thought to originate in fibroblasts of the tissues comprising tendons, ligaments, and muscles. Minimally responsive to conventional cytotoxic chemotherapies, >50% of SEF patients experience local recurrence and/or metastatic disease. SEF is most commonly discovered in middle-aged and elderly adults, but also rarely in children. A common gene fusion occurring between the EWSR1 and CREB3L1 genes has been observed in 80%-90% of SEF cases. We describe here the youngest SEF patient reported to date (a 3-yr-old Caucasian male) who presented with numerous bony and lung metastases. Additionally, we perform a comprehensive literature review of all SEF-related articles published since the disease was first characterized. Finally, we describe the generation of an SEF primary cell line, the first such culture to be reported. The patient described here experienced persistent disease progression despite aggressive treatment including multiple resections, radiotherapy, and numerous chemotherapies and targeted therapeutics. Untreated and locally recurrent tumor and metastatic tissue were sequenced by whole-genome, whole-exome, and deep-transcriptome next-generation sequencing with comparison to a patient-matched normal blood sample. Consistent across all sequencing analyses was the disease-defining EWSR1 - CREB3L1 fusion as a single feature consensus. We provide an analysis of our genomic findings and discuss potential therapeutic strategies for SEF., (© 2021 Woods et al.; Published by Cold Spring Harbor Laboratory Press.)

The tumor genome of a patient with advanced pancreatic cancer was sequenced to identify potential therapeutic targetable mutations after standard of care failed to produce any significant overall response. Matched tumor-normal whole-genome sequencing revealed somatic mutations in BRAF , TP53 , CDKN2A , and a focal deletion of SMAD4 The BRAF variant was an in-frame deletion mutation (ΔN486_P490), which had been previously demonstrated to be a kinase-activating alteration in the BRAF kinase domain. Working with the Novartis patient assistance program allowed us to treat the patient with the BRAF inhibitor, dabrafenib. The patient's overall clinical condition improved dramatically with dabrafenib. Levels of serum tumor marker dropped immediately after treatment, and a subsequent CT scan revealed a significant decrease in the size of both primary and metastatic lesions. The dabrafenib-induced remission lasted for 6 mo. Preclinical studies published concurrently with the patient's treatment showed that the BRAF in-frame mutation (ΔNVTAP) induces oncogenic activation by a mechanism distinct from that induced by V600E, and that this difference dictates the responsiveness to different BRAF inhibitors. This study describes a dramatic instance of how high-level genomic technology and analysis was necessary and sufficient to identify a clinically logical treatment option that was then utilized and shown to be of clinical value for this individual., (© 2019 Wrzeszczynski et al.; Published by Cold Spring Harbor Laboratory Press.)