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A Jewish couple of mixed origin was referred for genetic counseling following termination of pregnancy at 18 weeks of gestation due to severe ventriculomegaly with aqueduct stenosis. Trio exome sequencing revealed a loss‐of‐function heterozygous variant in the SMARCC1 gene inherited from an unaffected mother. The SMARCC1 gene is associated with embryonic neurodevelopmental processes. Recent studies have linked perturbations of the gene with autosomal dominant congenital hydrocephalus, albeit with reduced penetrance. However, these studies were not referenced in the SMARCC1 OMIM record (*601732) and the gene was not considered, at the time, an OMIM morbid gene. Following our case and appeal, SMARCC1 is now considered a susceptibility gene for hydrocephalus. This allowed us to reclassify the variant as likely pathogenic and empowered the couple to make informed reproductive choices. Key points: What's already known about this topic?In mice, SMARCC1 was shown to be important for proper proliferation of neural progenitor cells in the neural tube.In humans, SMARCC1 has been suggested as a risk gene for congenital hydrocephalus due to aqueduct stenosis.Until recently, SMARCC1 was not considered an OMIM morbid gene. What does this study add?Our report confirms the involvement of SMARCC1 haploinsufficiency in congenital hydrocephalus with aqueduct stenosis as well as additional brain malformations.We present the first evidence for findings consistent with holoprosencephaly due to SMARCC1 pathogenic variants.SMARCC1 has been upgraded to an OMIM susceptibility gene for hydrocephalus. [ABSTRACT FROM AUTHOR]

This article discusses the natriuretic peptide (NP) hormone system and its role in blood pressure regulation and cardiovascular disease. Specifically, it focuses on atrial natriuretic peptide (ANP) and its processing by the enzyme Corin. The article describes a study involving two siblings of Filipino descent who have a novel cardiovascular syndrome called CHAF-LA syndrome, which is caused by a loss-of-function variant in the CORIN gene. The study suggests that ANP plays a unique role in maintaining blood pressure and highlights the potential benefits of increasing ANP production in patients with Corin deficiency. The article also discusses the association between CHAF-LA syndrome and hypertension in the Filipino population and suggests further research is needed to understand the full extent of the disease. [Extracted from the article]

Fetal phenotype: A couple of Ashkenazi Jewish descent was referred for an early anatomy scan at 14 + 2 weeks of gestation following a previous pregnancy termination due to posterior encephalocele and enlarged kidneys. The index pregnancy was also positive for several fetal abnormalities, including enlarged kidneys with cystic dysplasia and abnormal cerebellar morphology highly suggestive of Joubert syndrome. Genetic diagnostic test performed, result, and interpretation: Trio exome sequencing revealed compound heterozygosity for variants in the TMEM67 gene: a known pathogenic maternally inherited variant found in trans with a paternal intronic variant of unknown significance. RNA analysis revealed that the intronic variant creates a cryptic acceptor splice site in intron 12, leading to the insertion of 22 bp and causing a frameshift with a premature stop codon. This analysis enabled the reclassification of the intronic variant to likely pathogenic. Implications and novelty: This information empowered the couple to make informed reproductive choices and opt for preimplantation genetic testing (PGT) for future pregnancies. Key points: What's already known about this topic?Intronic variants are often classified as variants of unclear significance (VUS). What does this study add?This report highlights the importance of RNA analysis in cases where an intronic VUS is found in trans with a pathogenic or likely pathogenic variant in an autosomal recessive gene compatible with the fetal phenotype. [ABSTRACT FROM AUTHOR]

Key points: What's already known about this topic? Genetic lymphatic disorders are a common cause of non‐immune hydrops fetalis, with PIEZO1 being one of the more recently established disease‐causing genes. What does this study add? Disease‐causing PIEZO1 variants have mostly been reported as single nucleotide variants or small indels. We report on a fetus with compound heterozygous deletions within and including PIEZO1. The deletions were not detected by chromosomal microarray (CMA).This case highlights the value of exome sequencing in detecting copy number variants that are below CMA resolution. [ABSTRACT FROM AUTHOR]

Tel Hashomer camptodactyly syndrome is a long‐known entity characterized by camptodactyly with muscular hypoplasia, skeletal dysplasia, and abnormal palmar creases. Currently, the genetic basis for this disorder is unknown, thus there is a possibility that this clinical presentation may be contained within another genetic diagnosis. Here, we present a multiplex family with a previous clinical diagnosis of Tel Hashomer camptodactyly syndrome. Whole exome sequencing and pedigree‐based analysis revealed a novel hemizygous truncating variant c.269_270dup (p.Phe91Alafs*34) in the FGD1 gene (NM_004463.3) in all three symptomatic patients, congruous with a diagnosis of Aarskog–Scott syndrome. Our report adds to the limited data on Aarskog–Scott syndrome, and emphasizes the importance of unbiased comprehensive molecular testing toward establishing a diagnosis for genetic syndromes with unknown genetic basis. [ABSTRACT FROM AUTHOR]

The current outbreak of the novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), causing coronavirus disease 2019 (COVID-19), has become a worldwide pandemic with high morbidity and mortality in individuals with chronic disorders.1 The pandemic introduced many unanticipated challenges for patients with chronic and rare diseases, such as Gaucher disease (GD).2 GD is the most common inborn error of metabolism, caused by biallelic glucosylceramidase beta ( I GBA i ) variants and affecting the recycling of cellular glycolipids; GD manifests as hepatosplenomegaly, thrombocytopenia, anaemia and bone disease.3 We performed a cross-sectional study using an online survey regarding attitudes of GD experts towards COVID-19 vaccination for patients with GD, and the impact of the pandemic on their patients. Overall, our present findings can assist in reassuring patients with GD worldwide of the expected mild nature of COVID-19, in supporting of COVID-19 vaccination and informing of their conduct during the pandemic. Gaucher disease (GD) expert views on COVID-19 vaccination for patients with GD. [Extracted from the article]

Agenesis of the corpus callosum (ACC) is a common prenatally‐detected brain anomaly. Recently, an association between mutations in the DCC Netrin 1 receptor (DCC) gene and ACC, with or without mirror movements, has been demonstrated. In this manuscript, we present a family with a novel heterozygous frameshift mutation in DCC, review the available literature, and discuss the challenges involved in the genetic counseling for recently discovered disorders with paucity of medical information. We performed whole exome sequencing in a healthy nonconsanguineous couple that underwent two pregnancy terminations due to prenatal diagnosis of ACC. A heterozygous variant c.2774dupA (p.Asn925Lysfs*17) in the DCC gene was demonstrated in fetal and paternal DNA samples, as well as in a healthy 4‐year‐old offspring. When directly questioned, both father and child reported having mirror movements not affecting quality of life. Segregation analysis demonstrated the variant in three paternal siblings, two of them having mirror movements. Brain imaging revealed normal corpus callosum. Summary of literature data describing heterozygous loss‐of‐function variants in DCC (n = 61) revealed 63.9% penetrance for mirror movements, 9.8% for ACC, and 5% for both. No significant neurodevelopmental abnormalities were reported among the seven published patients with DCC loss‐of‐function variants and ACC. Prenatal diagnosis of ACC should prompt a specific anamnesis regarding any neurological disorder, as well as intentional physical examination of both parents aimed to detect mirror movements. In suspicious cases, detection of DCC pathogenic variants might markedly improve the predicted prognosis, alleviate the parental anxiety, and possibly prevent pregnancy termination. [ABSTRACT FROM AUTHOR]

Constitutional mismatch repair deficiency (CMMRD) is caused by germline pathogenic variants in both alleles of a mismatch repair gene. Patients have an exceptionally high risk of numerous pediatric malignancies and benefit from surveillance and adjusted treatment. The diversity of its manifestation, and ambiguous genotyping results, particularly from PMS2, can complicate diagnosis and preclude timely patient management. Assessment of low‐level microsatellite instability in nonneoplastic tissues can detect CMMRD, but current techniques are laborious or of limited sensitivity. Here, we present a simple, scalable CMMRD diagnostic assay. It uses sequencing and molecular barcodes to detect low‐frequency microsatellite variants in peripheral blood leukocytes and classifies samples using variant frequencies. We tested 30 samples from 26 genetically‐confirmed CMMRD patients, and samples from 94 controls and 40 Lynch syndrome patients. All samples were correctly classified, except one from a CMMRD patient recovering from aplasia. However, additional samples from this same patient tested positive for CMMRD. The assay also confirmed CMMRD in six suspected patients. The assay is suitable for both rapid CMMRD diagnosis within clinical decision windows and scalable screening of at‐risk populations. Its deployment will improve patient care, and better define the prevalence and phenotype of this likely underreported cancer syndrome. [ABSTRACT FROM AUTHOR]

MYH7‐related disease (MRD) is the most common hereditary primary cardiomyopathy (CM), with pathogenic MYH7 variants accounting for approximately 40% of familial hypertrophic CMs. MRDs may also present as skeletal myopathies, with or without CM. Since pathogenic MYH7 variants result in highly variable clinical phenotypes, from mild to fatal forms of cardiac and skeletal myopathies, genotype–phenotype correlations are not always apparent, and translation of the genetic findings to clinical practice can be complicated. Data on genotype–phenotype correlations can help facilitate more specific and personalized decisions on treatment strategies, surveillance, and genetic counseling. We present a series of six MRD pedigrees with rare genotypes, encompassing various clinical presentations and inheritance patterns. This study provides new insights into the spectrum of MRD that is directly translatable to clinical practice. [ABSTRACT FROM AUTHOR]