Child with a mild CHIME syndrome phenotype and carrying a novel p.(Asp52Asn) <i>PIGL</i> pathogenic variant in association with the previously reported p.(Leu167Pro) variant: A case report

Rolland, Marion; Dubourg, Christèle; Cospain, Auriane; Droitcourt, Catherine; Pasquier, Laurent

doi:10.1111/pde.14969

Cited by 5 publications

(1 citation statement)

References 17 publications

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“…To further investigate the likely causative role of PIGW variants, we compared the prenatal findings associated with PIGW with those reported for the others PIG/PGAPs . (Table 2) 13–32 , 36–51 . Based on selected articles, phenotypic comparison is possible mostly for PIGW , PIGN , PIGV and PIGA , for which the description of prenatal manifestations is available.…”

Section: Discussionmentioning

confidence: 99%

Prenatal ultrasound findings associated with PIGW variants: One more piece in the FRYNS syndrome puzzle? PIGW‐related prenatal findings

et al. 2022

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Objective We describe the prenatal ultrasound findings and autopsy of three fetuses with multiple congenital anomalies (MCA) whose diagnostic workup suggested the same genetic etiology. We conducted a literature review to corroborate the molecular results and find evidence that the identified variants are responsible for the phenotype seen. Methods Trio‐based Exome Sequencing (ES) analysis was performed on chorionic villus samples. We reviewed available reports dealing with prenatal manifestations of genes involved in the Glycosylphosphatidylinositols (GPI) biosynthesis defects (GPIBDs). Results Prenatal findings shared by all the three pregnancies included facial dysmorphisms, brain malformations of the posterior fossa, skeletal and genitourinary anomalies. ES analysis identified homozygous variants of uncertain significance in PIGW in the three fetuses. Prenatal findings of the three pregnancies overlapped with those previously described for PIGW variants and with those associated with PIGN, PIGV and PIGA variants. Conclusion Based on the phenotypic overlap between the prenatal findings in our three cases and other cases with pathogenic variants in other genes involved in GPIBDs, we speculate that the variants identified in the three fetuses are likely causal of their phenotype and that the PIGWclinical spectrum might extend to MCA, mainly involving brain, skeletal and genitourinary systems. Moreover, we suggest that also PIGW could be involved in Fryns/Fryns‐like phenotypes.

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Section: Discussionmentioning

confidence: 99%

Prenatal ultrasound findings associated with PIGW variants: One more piece in the FRYNS syndrome puzzle? PIGW‐related prenatal findings

et al. 2022

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CHIME Syndrome in a Child With Homozygous PIGL p.Leu167Pro Variant

Arany,

Zocche,

Mellerio

et al. 2024

American J of Med Genetics Pt A

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CHIME syndrome is a variable condition characterized by ichthyosiform dermatosis, accompanied by intellectual disability, ocular colobomas, ear anomalies, and heart defects. It is an autosomal recessive condition caused by biallelic pathogenic variants in the PIGL gene. Until now, all reports of individuals affected with CHIME syndrome showed the PIGL c.500T>C p.Leu167Pro DNA variant on one allele of the PIGL gene, in combination with another PIGL DNA variant on the other allele. This has led to the hypothesis that the p.Leu167Pro variant determines to a mild phenotypic effect only and that the core phenotype is determined by the second PIGL DNA variant. We report the first individual with CHIME syndrome, a 6‐year‐old girl, with homozygous PIGL p.Leu167Pro variants, defusing this hypothesis as she is not mildly affected. As CHIME is a very rare condition, it is expected that a significant proportion of cases will be due to homozygous gene variants, especially of founder DNA variants, and offspring of consanguineous parents. We speculate that the lack of homozygous p.Leu167Pro DNA variants so far has been due to chance and that other homozygous cases will be identified in future reports of affected individuals.

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Child with a mild CHIME syndrome phenotype and carrying a novel p.(Asp52Asn) PIGL pathogenic variant in association with the previously reported p.(Leu167Pro) variant: A case report

Rolland

Dubourg

Cospain

et al. 2022

Pediatric Dermatology

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Coloboma, congenital heart disease, ichthyosiform dermatosis, mental retardation, and ear anomalies (CHIME) syndrome is a very rare autosomal recessive neuroectodermal disorder that was initially described by Zunich and Kaye in 1983. 1 This disease entity is related to pathogenic variants in the gene coding for the phosphatidylinositol glycan anchor biosynthesis class L (PIGL) protein (OMIM #280000), an enzyme located at the membrane of the endoplasmic reticulum. PIGL catalyzes the second step in glycosylphosphatidylinositol (GPI) biosynthesis, that is, the de-N-acetylation of N-acetylglucosaminyl-phosphatidylinositol. 2 GPI has a critical role in the anchoring of many membrane proteins, some of which are involved in neurogenesis. 3 To date, only eight cases of CHIME syndrome in people with confirmed PIGL variants have been reported. [4][5][6] Given the rarity of this syndrome, data on its clinical features and clinical spectrum are scarce. All six of the cases reported by Ng et al. 4 carried a compound heterozygous variant c.500T>C, p.(Leu167Pro). A second pathogenic variant was identified in 5 of the 6 patients. 4 In the seventh case of PIGL-related CHIME syndrome (reported by Knight Johnson et al. 5 ), the c.500T>C, p.(Leu167Pro) variant was again detected on the first allele but the second allele carried an intragenic deletion of PIGL's exons 4-6. In the eighth case (reported

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Child with a mild CHIME syndrome phenotype and carrying a novel p.(Asp52Asn) PIGL pathogenic variant in association with the previously reported p.(Leu167Pro) variant: A case report

Cited by 5 publications

References 17 publications

Prenatal ultrasound findings associated with PIGW variants: One more piece in the FRYNS syndrome puzzle? PIGW‐related prenatal findings

Prenatal ultrasound findings associated with PIGW variants: One more piece in the FRYNS syndrome puzzle? PIGW‐related prenatal findings

CHIME Syndrome in a Child With Homozygous PIGL p.Leu167Pro Variant

Child with a mild CHIME syndrome phenotype and carrying a novel p.(Asp52Asn) PIGL pathogenic variant in association with the previously reported p.(Leu167Pro) variant: A case report

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