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Whereas truncating variants of the giant protein Titin (TTNtv) are the main cause of familial dilated cardiomyopathy (DCM), recently Filamin C truncating variants (FLNCtv) were identified as a cause of arrhythmogenic cardiomyopathy (ACM). Our aim was to characterize and compare clinical and MRI features of TTNtv and FLNCtv in the Belgian population. In index patients referred for genetic testing of ACM/DCM, FLNCtv and TTNtv were found in 17 (3.6%) and 33 (12.3%) subjects, respectively. Further family cascade screening yielded 24 and 19 additional truncating variant carriers in FLNC and TTN, respectively. The main phenotype was ACM in FLNCtv carriers whereas TTNtv carriers showed either an ACM or DCM phenotype. Non-sustained Ventricular Tachycardia was frequent in both populations. MRI data, available in 28/40 FLNCtv and 32/52 TTNtv patients, showed lower Left Ventricular (LV) ejection fraction and lower LV strain in TTNtv patients (p < 0.01). Conversely, both the frequency (68% vs 22%) and extent of non-ischemic myocardial late gadolinium enhancement (LGE) was significantly higher in FLNCtv patients (p < 0.01). Hereby, ring-like LGE was found in 16/19 (84%) FLNCtv versus 1/7 (14%) of TTNtv patients (p < 0.01). In conclusion, a large number of FLNCtv and TTNtv patients present with an ACM phenotype but can be separated by cardiac MRI. Whereas FLNCtv patients often have extensive myocardial fibrosis, typically following a ring-like pattern, LV dysfunction without or limited replacement fibrosis is the common TTNtv phenotype., (© 2023. The Author(s), under exclusive licence to European Society of Human Genetics.)

In the vast majority of pediatric patients with dilated cardiomyopathy, the specific etiology is unknown. Studies on families with dilated cardiomyopathy have exemplified the role of genetic factors in cardiomyopathy etiology. In this study, we applied whole-exome sequencing to members of a non-consanguineous family affected by a previously unreported congenital dilated cardiomyopathy syndrome necessitating early-onset heart transplant. Exome analysis identified compound heterozygous variants in the FLNC gene. Histological analysis of the cardiac muscle demonstrated marked sarcomeric and myofibrillar abnormalities, and immunohistochemical staining demonstrated the presence of Filamin C aggregates in cardiac myocytes. We conclude that biallelic variants in FLNC can cause congenital dilated cardiomyopathy. As the associated clinical features of affected patients are mild, and can be easily overlooked, testing for FLNC should be considered in children presenting with dilated cardiomyopathy., Competing Interests: The authors declare no conflict of interest. DMB and CB are compensated and serve as the chief medical officer and the laboratory director of Gene by Gene, respectively.

Loss-of-function mutations in filamin A (FLNA) cause an X-linked dominant disorder with multiple organ involvement. Affected females present with periventricular nodular heterotopia (PVNH), cardiovascular complications, thrombocytopenia and Ehlers-Danlos syndrome. These mutations are typically lethal to males, and rare male survivors suffer from failure to thrive, PVNH, and severe cardiovascular and gastrointestinal complications. Here we report two surviving male siblings with a loss-of-function mutation in FLNA. They presented with multiple complications, including valvulopathy, intestinal malrotation and chronic intestinal pseudo-obstruction (CIPO). However, these siblings had atypical clinical courses, such as a lack of PVNH and a spontaneous improvement of CIPO. Trio-based whole-exome sequencing revealed a 4-bp deletion in exon 40 that was predicted to cause a lethal premature protein truncation. However, molecular investigations revealed that the mutation induced in-frame skipping of the mutated exon, which led to the translation of a mutant FLNA missing an internal region of 41 amino acids. Functional analyses of the mutant protein suggested that its binding affinity to integrin, as well as its capacity to induce focal adhesions, were comparable to those of the wild-type protein. These results suggested that exon skipping of FLNA partially restored its protein function, which could contribute to amelioration of the siblings' clinical courses. This study expands the diversity of the phenotypes associated with loss-of-function mutations in FLNA.

Mutations of FLNA, an X-linked gene that encodes the cytoskeletal protein filamin A, cause diverse and distinct phenotypes including periventricular nodular heterotopia and otopalatodigital spectrum disorders (OPDS). Craniofacial abnormalities associated with OPDS include supraorbital hyperostosis, down-slanting palpebral fissures and micrognathia; craniosynostosis was previously described in association with FLNA mutations in two individual case reports. Here we present four further OPDS subjects who have pathological FLNA variants and craniosynostosis, supporting a causal link. Together with the previously reported patients, frontometaphyseal dysplasia was the most common clinical diagnosis (four of six cases overall); five patients had multiple suture synostosis with the sagittal suture being the most frequently involved (also five patients). No genotype-phenotype correlation was evident in the distribution of FLNA mutations. This report highlights the need to consider a filaminopathy in the differential diagnosis of craniosynostosis, especially in the presence of atypical cranial or skeletal features.