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Correspondence on “Disorder of sex development associated with a novel homozygous nonsense mutation in COG6 expands the phenotypic spectrum of COG6‐CDG”

To the Editor, We are writing about the paper “Disorder of sex development associated with a novel homozygous nonsense mutation in COG6 expands the phenotypic spectrum of COG6-CDG,” in which we described a Moroccan patient with a novel NM_020751(COG6): c.782T>A homozygous variant in the COG6 gene, presenting a disorder of sexual differentiation in addition to severe manifestations of the COG6-CDG (OMIM #614576) clinical spectrum (Lubbehusen et al., 2010; Lugli et al., 2021; Mandel et al., 2020; Rymen et al., 2015; Zeevaert et al., 2008). The patient's brother, who died of respiratory insufficiency at 1 year of age in Morocco, presented with a similar phenotype, but had not previously been evaluated for the COG6 variant (Figure 1). Recently, we found that a DNA sample from the affected brother was still stored in a laboratory where some genetic analyses had been carried out and found to be normal (karyotype, CGH-array, DNA methylation analysis for Prader-Willi/ Angelman syndromes and sequencing analysis of the PMM2 gene). Sequencing analysis of the familial COG6 variant revealed that this infant was homozygous for the NM_020751(COG6): c.782T>A nucleotide change leading to the nonsense p.(Leu261*) variant. The child was born at 37 weeks of gestational age by urgent cesarean section due to abnormal cardiotocography and intrauterine growth retardation (weight 1900 g, first centile; length 41.7 cm, first centile; occipital frontal circumference 31 cm, first centile). Apgar scores were 4, 7, and 8 at 1, 5, and 10 min, respectively. The child presented hypotonia, poor feeding, microcephaly, dysmorphic facial features (bitemporal narrowing, high anterior hairline, spars hair, low set ears, thin upper lip, mild micrognathia), camptodactyly of the thirdfourth and fifth finger bilaterally, micropenis and cryptorchidism, umbilical and inguinal hernias, bilateral clubfoot, stenosis of the left branch of the pulmonary artery, cerebellar hypoplasia, coagulation disorder, elevated liver enzymes, and splenomegaly (Lugli et al., 2021). As part of their phenotype, we found a sexual differentiation disorder in both siblings, manifesting in the older child with micropenis/cryptorchidism and in the younger with female-like genitalia (Lugli et al., 2021). At that time, sexual differentiation disorder in COG6-CDG was completely unexpected, based on the literature. Hence, in our opinion, these additional observations contribute to better delineate a genotypic/phenotypic spectrum in COG6-CDG and provide further evidence to support the hypothesis that sexual differentiation in our patients is a manifestation of COG6-CDG instead of a co-occurrence. Recently, ambiguous genitalia have been reported in two siblings suffering from COG6-CDG, both found homozygous for a 26 base pair deletion in the COG6 gene (Mandel et al., 2020). To the best of our knowledge, the COG6 c.782T>A p.(Leu261*) variant should be considered causative of a severe multisystem COG6-CDG phenotype with additional disorders of sexual development (Kubota et al., 2005; Lugli et al., 2021). Therefore, we strengthen our hypothesis that this COG6 variant could interfere with glycosylation processes that are fundamental for systemic cell functioning and, most specifically, for gonad migration and genitalia morphogenesis.