A novel HECW2 variant in an infant with congenital long QT syndrome

Pathogenic variants of HECW2 have been reported in cases of neurodevelopmental disorder with hypotonia, seizures, and absent language (NDHSAL; OMIM #617268). A novel HECW2 variant (NM_001348768.2:c.4343 T > C,p.Leu1448Ser) was identified in an NDHSAL infant with severe cardiac comorbidities. The patient presented with fetal tachyarrhythmia and hydrops and was postnatally diagnosed with long QT syndrome. This study provides evidence that HECW2 pathogenic variants can cause long QT syndrome along with neurodevelopmental disorders.

was suspected, and the fetal heart rate was closely monitored.Ultrasound examination at 27 weeks of gestation revealed fetal hydrops, most likely resulting from tachycardia.After confirming that the maternal electrocardiogram (ECG) was normal, transmaternal treatment was initiated with digoxin followed by sotalol.However, the fetus remained in intermittent tachycardia.A 1689 g female neonate was delivered by cesarean section at 33 weeks of gestation due to maternal drug intolerance.A postnatal ECG demonstrated prolongation of the corrected QT interval (QTc [Fridericia], 682 msec) and torsade de pointes (Fig. 2A), which led to a diagnosis of congenital LQTS.
The patient was started on a regimen of magnesium sulfate and landiolol, which eliminated the torsade de pointes.Thereafter, treatment with mexiletine and propranolol gradually shortened the QT interval and effectively prevented ventricular tachycardia (Fig. 2B).The patient is still on medical therapy at 2 years of age and remains free of cardiac events.Neurological examinations revealed muscle hypotonia.At 3 months of age, the patient developed epileptic spasms.The interictal electroencephalography (EEG) results indicated hypsarrhythmia.The epileptic seizures were refractory to anti-seizure medication.Psychomotor development was severely delayed with no head control, eye pursuit, or speech sounds.The patient was fed via a gastrostomy tube due to feeding problems.Brain magnetic resonance imaging scans performed at 5 months of age showed no abnormal findings (Supplementary Fig. 1).These clinical features including hypotonia, seizures, and profound developmental delay were compatible with those of NDHSAL.
To reveal the underlying genetic etiology, the genomic DNA of the patient and the patient's parents was extracted from the peripheral blood after obtaining written informed consent.This study was approved by the Asahikawa Medical University Research Ethics Committee (approval number 17112).Genetic testing for the known LQTS-associated genes identified no pathogenic variants in this patient 7 .Next, whole exome sequencing and variant filtering analysis were performed on the genes of the patient-parent trio, which identified a de novo heterozygous missense variant in HECW2, NM_001348768.2:c.4343T > C,p.(Leu1448Ser).This missense variant was located in the C-terminal HECT domain of HECW2 and has been reported in another patient with NDHSAL in ClinVar (VCV001320205.1).A different missense change at the same codon (p.Leu1448Trp) has also been reported as likely pathogenic (ClinVar ID: VCV000801845.1) 8.This missense variant was absent from the controls in public databases, such as the Exome Variant Server (http:// evs.gs.washington.edu/EVS/),dbSNP (http://www.ncbi.nlm.nih.gov/snp/), and Genome Aggregation Database (gnomAD, https:// gnomad.broadinstitute.org/).It was predicted to be damaged by in silico tools including SIFT, PolyPhen-2, and CADD (score 29.6).According to the American College of Medical Genetics and Genomics guidelines 9 , the variant was classified as pathogenic (PS2, PM1, PM2, PM5, PP3, and PP4).
In the present case, LQTS was diagnosed based on a prolonged QT interval and history of torsade de pointes.The patient harbored no pathogenic variants in the known LQTS-associated genes, but a pathogenic variant in HECW2.Cardiac comorbidities were reported in four cases of HECW2-related disorders (Supplementary Table 1).The first reported case of HECW2-related disorder with LQTS had prenatal-onset cardiomyopathy and harbored the heterozygous missense variant in EIF2B2, p.(Gly200Val), in addition to HECW2 variant, NM_001348768.2:c.4334A > G,p.(Glu1445Gly) 5 .Recessive variants in EIF2B2 cause early onset vanishing white matter disease; however, heterozygous carriers of EIF2B2 variants are asymptomatic 10 .Thus, the cardiac phenotype of the patient was considered to be due to HECW2 variant.This is the second case that considers LQTS as a possible phenotype of a HECW2 variant.Ubiquitylation has been shown to be implicated in the regulation of cardiac ion channels 11,12 .HECW2 is a member of the neuronal precursor cellexpressed developmentally down-regulated protein 4 (Nedd4)  family of E3 ubiquitin ligases, which comprises nine members, including Nedd4-2.In particular, Nedd4-2 has been shown to regulate cell surface expression of cardiac voltage-gated sodium channel Na v 1.5 through post-translational modification 11 .Nedd4-2 deficiency increases the cell surface expression of Na v 1.5, resulting in cardiac proarrhythmic changes such as a prolonged QT interval 12 .LQTS patients with gain-of-function mutations of SCN5A, the gene encoding Na v 1.5, have been reported to benefit from sodium channel blockers 13 .In the present case with HECW2 variant, the use of mexiletine, a voltage-gated sodium channel blocker, in combination with a beta-blocker was effective in shortening the QT interval and suppressing cardiac events.Both HECW2 and Nedd4-2 are highly expressed in the heart tissue.Thus, future studies are required to elucidate the cardiac targets of HECW2.In conclusion, this study reports an additional case of a HECW2-related disorder with cardiac involvement and provides further evidence that the clinical manifestations of this disorder are not confined to the central nervous system.

HGV DATABASE
The relevant data from this Data Report are hosted at the Human Genome Variation Database at https://doi.org/10.6084/m9.figshare.hgv.3305.

Fig. 1
Fig. 1 Fetal echocardiogram.2D mode (upper) shows the ultrasound line used for M-mode (lower) echocardiogram crossing the left atrium (LA) and the right ventricle (RV).M-mode shows tachycardia with a heart rate at 190 beats per minute.LA left atrium, LV left ventricle, RA right atrium, RV right ventricle.

Fig. 2
Fig. 2 Postnatal electrocardiogram (ECG).A monitor ECG at 3 h after birth showing torsades de pointes.B Serial ECG showing that antiarrhythmic drug therapy shortened the corrected QT interval (QTc) according to the Fridericia formula.