Expanding <i>PIGM</i>‐related disorders to coding mutations

Glycosylphosphatidylinositol (GPI) is a complex glycolipid that anchors over 150 proteins to the cell membrane surface. To date, over 20 genes (PIG_ and PGAP2 genes below) involved in the synthesis of the GPI-anchor have been associated with a group of Mendelian multisystem disorders known as inherited GPI deficiencies (IGD) and belonging to the broader group of congenital disorders of glycosylation. Among them, glycosylphosphatidylinositol biosynthesisdefect-1 (GPIBD1, MIM610293) is an autosomal recessive condition related to PIGM.1 To date, eight patients have been reported. Seven patients have presented with thrombophilia leading to cerebral and portal vein thrombosis, seizures, macrocephaly and thrombocytopenia starting from the age of 5 months, and they carry a recurrent homozygous noncoding variant in the promoter region of PIGM.2-4 The last patient carries a homozygous missense variant in PIGM. He presented with dermatological and craniofacial features, portal vein thrombosis, rapidly progressive and fatal multicystic encephalomalacia with ventriculomegaly and suppression burst at EEG.1 We report 2 additional patients, carrying coding variants in PIGM, with a multiple congenital anomaly and intellectual disability (MCA)-ID syndrome characterized by ichthyosis, redundant skin folds, severe encephalopathy and craniofacial anomalies (Table 1 and Figure 1) being the severe end of the spectrum of PIGM gene-related anomalies. Patient 1 died of sepsis at 5 weeks of age. Patient 2 is now 7 years old. No weight gain, died at 5 weeks of age from sepsis. Steatosis and no other malformation at autopsy Normal growth (H: 60th c., W: 90th c., OFC: 96th c.) at 6 years Cardiomegaly from 5 years with normal EKG except for repolarization abnormality Walking unaided at 2 years, poor eye contact and < 100 spoken words at 7 years, episodes of pneumonia requiring BIPAP c.1254_1257del, p.(Arg419Serfs*81)pat Frequency in genomADv4: 0.000115 and no homozygotes c.1111 T > C, p.(Trp371Arg)mat not reported c.1254_1257del, p.(Arg419Serfs*81)mat Frequency in genomADv4: 0.000115 and no homozygotes c.402C > A, p.(Asn134Lys) pat Frequency in genomADv4: 0.000002703 in non-Finnish Europeans Both patients presented with variable congenital epidermal manifestations associating severe and diffuse ichthyosis, squamous plaques on eyelids, trunk and arms with yellowish to brown skin in patient 1 (Figure 1a,b) and fine scales on erythematous skin in patient 2. Brady et al. reported thickened, lichenified and orange peel-like skin.1 Wrinkling of the skin was either diffuse (patient 1, Figure 1c) or limited to forehead and midface (patient 2). In the latter, skin became dry (cheeks, auricular folds), with scaling areas on the dorsum of hands and feet mostly in winter from 2 years. Skin biopsy, taken in patient 1, showed ichthyotic changes (Figure 1d,e). Normal skin reported with noncoding mutations in PIGM is surprising considering the decreased expression of total GPI and CD59 in fibroblasts.4 The residual expression of PIGM mRNA in fibroblasts compared to blood cell suggests a quantitative threshold for skin manifestation2, 3 as skin involvement in both patients is most likely the consequence of GPI biosynthesis deregulation. Skin manifestations are reported in IGD: onychodystrophy (PIGY), palmoplantar keratoderma (PIGO) and ichthyosiform dermatosis (GPIBD5, MIM28000).5 Epidermal-specific knockout of PigA in mice mimics human Harlequin ichthyosis.6 Altogether, epidermal involvement (ichthyosis +/− palmoplantar keratoderma) is more frequent than dermal involvement (soft and sagging skin or cutis laxa) reported only with PIGO, PIGM and possibly PIGQ mutations. Cleft palate (patient 1) is reported with PIGM, PGAP2, PIGV, PIGO and PIGN mutations.5-9 Both Trp371 and Asn134 are highly conserved amino acids of PIGM. Trp371 lies in the mannosyltransferase domain of the protein and Asn134 at a transmembrane cytoplasmic loop. Both variants are classified damaging or probably damaging by most prediction tools. Moderate decrease for total GPI anchor validated the pathogenic nature of the variants (Figure 1f). The recurrent deletion of four nucleotides should escape nonsense-mediated decay as it lies in the last exon. It is presumed to elongate the protein and replace the last 5 amino acids of the normal PIGM protein by 80 incorrect ones and could lead to a stable protein retaining some function. Thus, a more severe phenotype could be expected in patient(s) with biallelic loss-of-function variants. Many examples illustrates the concept of tissue-specific deregulation of a gene leading to endophenotypes from the full-blown spectrum of features ascribed to coding sequence mutations. PIGM can be added to the list with the particularity of full-blown presentation being described second. We thank the families for their participation, MSDAvenir (Devo-Decode project) and the Philanthropy Department of Mutuelles AXA (Head and Heart Chair) for their support. None. The authors declare no conflicts of interest. The patient's parents in this manuscript have given written informed consent to the publication of their case details. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

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