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Microdeletion 1q44 on the long arm of chromosome 1 leads to a phenotype that includes microcephaly, seizure, agenesis or hypogenesis of the corpus callosum, polydactyly, congenital heart defects and severe developmental delay along with characteristic facial dysmorphic signs. Until today, the distinct genetic causes for the different symptoms remain unclear. We here report a 1.2 Mb de novo microdeletion 1q44 identified by performing a SNP array analysis. The female patient presented with microcephaly, seizure, hypogenesis of corpus callosum, postaxial hexadactyly, an atrial septal defect, a ventricular septal defect, hypertelorism, a long and smooth philtrum, thin vermilion borders, and micrognathia, all common features of microdeletion 1q44. An additionally performed chromosome analysis excluded any chromosomal rearrangements. The deleted region included the genes ZBTB18 as well as HNRNPU amongst others. Both are possibly candidate genes for the dysgenesis of the corpus callosum. AKT3 , another candidate gene, was not affected by the deletion in this patient. Thus, the genetic findings in this case report spotlight ZBTB18 and HNRNPU in the genesis of the typical microdeletion 1q44 symptoms, especially concerning the dysgenesis of the corpus callosum, and therefore could help to unveil more of the genetic background of this syndrome. [ABSTRACT FROM AUTHOR]

• Arrhythmogenic cardiomyopathy (ACM) is not restricted to the right ventricle. • Signs of myocarditis can be the first symptom of ACM, especially when caused by variants in DSP. • The current Task Force Criteria for diagnosing ACM are in need for revision. • Genetic testing should be performed in patients with (recurrent) virus-negative myocarditis. Arrhythmogenic right ventricular cardiomyopathy (ARVC) is now usually referred to as arrhythmogenic cardiomyopathy (ACM) because of the possible left and biventricular affection. In recent years, it has been shown that early-stage ACM, especially in women carrying a disease-causing variant in the DSP gene, may present with clinical signs of myocarditis. The female patient was diagnosed with myocarditis based on arrhythmia and findings on magnetic resonance imaging at the age of 24 years. An additional performed myocardial biopsy confirmed a lymphocytic inflammatory reaction. Subsequently, the patient experienced cardiac arrest because of ventricular fibrillation and was resuscitated. As a result, she received an implantable cardioverter defibrillator, and repeated ablations of recurrent ventricular tachycardia were performed. After four years, molecular genetic testing identified the heterozygous, likely pathogenic nonsense variant c.4789G > T, p.(Glu1597*) in DSP (NM_004415.4). Based on this finding, ACM could be diagnosed, and a heart transplantation was performed only a few months later because of rapid disease progression. Truncating variants in DSP have been associated with fulminant progression of arrhythmia. However, the currently used ARVC task force criteria are inadequate to detect DSP -associated ACM with left dominant presentation. Moreover, the initial diagnosis of myocarditis may distract from a more extensive search for other causes. Consequently, in cases of recurrent or unusually prolonged myocarditis, especially if present without detected pathogens, molecular genetic testing should be considered. [ABSTRACT FROM AUTHOR]

• Variants in TAB2 can cause isolated or syndromic CHD. • TAB2 -associated CHD has variable expressivity as well as reduced penetrance. • There is no clear genotype-phenotype correlation. Congenital heart defects (CHD) are the most common birth defect and disease-causing variant in TAB2 have found to be associated with isolated CHD. Recently, it became evident that pathogenic, mostly loss-of-function variants in TAB2 can also cause syndromic CHD that includes connective tissue anomalies. The number of published cases is limited posing a challenge for counseling affected patients and their relatives. Cases in whom whole exome sequencing was executed at our institute between January 2015 and June 2021 were screened for disease-causing variants in TAB2. Additionally, a PubMed-based review of the literature was performed in December 2021 in order to give an updated clinical overview of the TAB2 -associated phenotypic spectrum, including our cases. We identified three cases with syndromic CHD caused by different heterozygous loss-of-function variants in TAB2. In one of these cases, the variant was inherited by a healthy father. A comparison with published cases highlights that most patients were affected by structural and/or arrhythmic heart disease (about 90%) while about two third of all cases had syndromic comorbidity especially connective tissue defects and dysmorphic abnormalities. Our findings indicate a variable expressivity as well as reduced penetrance of TAB2 -associated CHD. Disease-causing variants in TAB2 should be considered in cases with isolated CHD but also in syndromic CHD with connective tissue abnormalities. However, prediction of the patients' clinical outcome solely based on the variant in TAB2 is still extremely challenging. [ABSTRACT FROM AUTHOR]

• We present the fifth case of MYO18B -associated disease with a previously unreported homozygous nonsense variant in MYO18B. • Prenatal features are described for the first time. • The core phenotype of MYO18B -associated disease comprises severe congenital myopathy with feeding difficulties in infancy and characteristic dysmorphic features. Homozygous loss-of-function variants in MYO18B have been associated with congenital myopathy, facial dysmorphism and Klippel-Feil anomaly. So far, only four patients have been reported. Comprehensive description of new cases that help to highlight recurrent features and to further delineate the phenotypic spectrum are still missing. We present the fifth case of MYO18B -associated disease in a newborn male patient. Trio exome sequencing identified the previously unreported homozygous nonsense variant c.6433C>T, p.(Arg2145*) in MYO18B (NM_032608.5). While most phenotypic features of our patient align with previously reported cases, we describe the prenatal features for the first time. Taking the phenotypic description of our patient into account, we propose that the core phenotype comprises a severe congenital myopathy with feeding difficulties in infancy and characteristic dysmorphic features. [ABSTRACT FROM AUTHOR]

• Cardiac-related secondary findings (SF) are identified in 1.4% (136/9962) of cases by exome sequencing (ES). • LDLR (24/136, 17.6%) and TTN (24/136, 17.6%) were the most frequently affected genes. • In 26.5% (36/136), findings would have been missed, if only index patients had been screened for SF in case of trio ES. Exome sequencing has been established as a fundamental tool in genetic diagnostics. It may also provide information about variants in genes unrelated to the primary purpose, so-called secondary findings. Especially, diagnoses of unnoticed inborn cardiac diseases are of high clinical relevance due to therapeutic options in context of prevention of sudden cardiac death. Exome data of 9962 individuals was analysed for relevant cardiogenetic findings. Genes were selected according to ACMG recommendations for secondary findings (v.3.1). First, a filter for (likely) pathogenic variants, published in the ClinVar database, was used. Second, exome data was screened for loss of function (LoF) variants in genes in which LoF is a known disease pathomechanism. All variants were evaluated by geneticists regarding their pathogenicity. Pathogenic or likely pathogenic variants were identified in 136 different individuals (136/9962, 1.4%), with the Low-Density Lipoprotein Receptor gene (LDLR , 24/136, 17.6%) and the Titin gene (TTN , 24/136, 17.6%), being the most frequently affected ones. 31.6% (43/136) of the identified variants had been reported beforehand, while 47.1% (64/136) had not been reported. The remaining cases (29/136, 21.3%) were part of research projects with no written reports. In 26.5% (36/136), the finding would have been missed, if only index patients and not their parents had been screened for secondary findings in case of trio ES. As demonstrated in our study, at least one or two out of one hundred people are likely to carry a pathogenic cardiogenetic variant. Counselling geneticist and clinicians need to be aware of these findings in exome and genome sequencing. Informed consent of the patient regarding the report of secondary findings should absolutely be obtained beforehand. [ABSTRACT FROM AUTHOR]