Balkan Journal of Medical Genetics

SEMILOBAR HOLOPROSENCEPHALY CAUSED BY A NOVEL AND DE NOVO ZIC2 PATHOGENIC VARIANT
Nonkulovski D1, Sofijanova A1, Spasovska T1, Gorjan Milanovski2, Muaremoska-Kanzoska Lj1, Arsov T2,3
*Corresponding Author: Prof Todor Arsov MD MGC PhD, Faculty of Medical Sciences, University Goce Delcev in Shtip, North Macedonia, E-mail: todor.arsov@ugd.edu.mk
page: 71

CASE PRESENTATION

We present the case of a 7-month old Caucasian female infant, from a well monitored twin pregnancy, gemellus II with intra-uterine growth restriction. The morphology scan at 20 weeks’ gestation revealed HPE and the parents were counselled about the clinical implications. The baby was delivered by caesarean section at 37 weeks’ gestation (weight 2700 g, body length 48 cm and APGAR score 7 and 8 at 1 and 5 minutes). The clinical examination by a neonatologist noted microcephaly with a head circumference of 28 cm at birth. The infant had mild facial dysmorphic features including hypertelorism and a narrow nasal bridge (Figure 1A). There were no findings of ambiguous genitalia. Neurological examination revealed central hypotonia and spasticity on all four extremities. The rest of the physical examination findings were unremarkable. Postnatal head ultrasonographic examination showed an absence of septum pellucidum, semilobar fusion of the hemispheres and mega cisterna magna (Figure 1B) and a brain MRI with FLAIR confirmed the diagnosis of HPE (Figure 2). Electroencephalography showed bihemispheric foci with a tendency for generalization (Figure 3) and transthoracic echocardiography revealed a subtle mid atrial septal defect, resulting in minimal L-D shunt and adequate kinetics of the heart. The abdominal ultrasonography was normal. Laboratory analyses revealed seropositivity for SARS-CoV-2, HSV and CMV, elevated alkaline phosphatase (303 U/L), non-significantly elevated arginine and C10 acylcarnitine and mild electrolyte disbalance (hypernatremia, hyperkalemia, hyperchloremia, hypercalcemia, hyperphosphatemia, hypermagnesemia). Genomic testing using a panel of 456 genes associated with brain malformations identified a novel and de novo pathogenic ZIC2 variant, initially interpreted as a variant of uncertain significance, and later reclassified as a likely pathogenic, according to the ACMG criteria.(24) This missense variant replaces amino acid cysteine at position 273 with tyrosine (Figure 4). The likely pathogenic missense ZIC2 variant c.818G>A (p.Cys273Tyr) was not present in either of the two parents, and biological paternity and maternity was deduced from the analysis of ultra-rare genetic variants found in the proband. The variant has not been described before in patients with HPE and has no frequency in the databases of human genetic variation (ExAC, gnomAD). Bioinformatic tools (SIFT, PolyPhen-2, Align-GVGD) predict this to be likely disruptive. Interestingly, the genetic analysis identified another ZIC2 variant (uncertain significance) c.1439C>T (p.Ser480Leu) in the proband, inherited from a healthy mother. The phase of the two variants could not be determined because the pathogenic variant occurred de novo. In addition, a number of additional variants of uncertain significance were identified (Table 1).

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