Phenotypic heterogeneity of POMT2 gene variants

To the Editor: We read with interest the article by Abdullah et al. (2017) about a 4-months-old male with Walker–Warburg syndrome (cerebellar malformations, retinal malformations, lissencephaly, muscular dystrophy) and left ventricular hypertrabeculation/noncompaction (LVHT) due to the compound heterozygous protein O-mannosyltransferase-2 (POMT2) variants p.Tyr666Cys, and p.His478Arg. The patient died at four months of age after three episodes of cardiac arrest precipitated by ventricular tachycardia (Abdullah et al., 2017). We have the following comments and concerns. Both parents were obviously heterozygous for one of the POMT2 variants each. Did either of the parents alsomanifest clinically with any phenotypic feature described previously in association with POMT2 gene mutations? Phenotypic features of POMT2 gene variants are listed in Table 1. POMT2 gene variants may manifest with isolated muscular dystrophy, isolated cerebral disease, but most frequently as multiorgan disorder affecting the brain, eyes, heart, kidneys, skin, bones, and muscles (Table 1). Though LVHT has not been previously reported in POMT2 gene mutation carriers, LVHT has been reported in other congenital muscular dystrophies, such as Fukuyama congenital muscular dystrophy (Amiya et al., 2016). If patients with a neuromuscular disorder are systematically investigated for LVHT, more than 80% of the patients may indeed present with this myocardial abnormality (Stöllberger, Finsterer, & Blazek, 2002). LVHT is frequently associated with endocardial or subendocardial fibrosis (Gerger et al., 2013). Endocardial or subendocardial fibrosis in the area of the cardiac conduction system is made responsible for the occurrence of life-threatening ventricular arrhythmias and sudden cardiac death. Did autopsy show these features? Cardiac MRI in LVHT patients may reveal late gadolinium enhancement (LGE) (Finsterer, Stöllberger, & Towbin, 2017) attributed to myocardial fibrosis. Was a cardiac MRI with contrast medium carried out and was LGE detected? Since LVHT occurs familiarly (Finsterer et al., 2017) and a causal relation with any of the genetic defects reported has not been proven thus far (Finsterer et al., 2017), it would be interesting to know if the mother and the father were also screened for LVHT by echocardiography or cardiac MRI. Did any of the two or their first degree relatives present with LVHT on cardiac imaging? Complications of LVHT may not only be ventricular arrhythmias but also heart failure, embolic stroke, and sudden cardiac death (Finsterer et al., 2017). Did any of these additional complications occur in the reported patient or any of the first degree relatives of the index case? Was heart failure attributed to LVHT, pulmonary hypertension, or to tachycardia? Contrary to the description in the discussion, Manzini et al., 2012 has not described three patientswith POMT2 genemutations but just a single patient (Abdullah et al., 2017). In summary, this study could be more meaningful if the parents would have been investigated for LVHT, if autopsy of the myocardium would be revised for the presence of endocardial or myocardial fibrosis, and if the available data about the patient would be systematically revised for the presence or absence of additional phenotypic features of POMT2 gene mutations, as listed in Table 1.