bims-meglyc 2026-04-12 papers

Issue of 2026–04–12
four papers selected by
Silvia Radenkovic, UMC Utrecht

HGG Adv. 2026 Apr 03. pii: S2666-2477(26)00044-8. [Epub ahead of print] 100604

A Homozygous Nonsense Variant in the Oligosaccharyltransferase Complex Gene, RPN1, Causes a Congenital Disorder of Glycosylation.

Bobby G Ng, Wenyue Zhang, Jennifer E Neil, Marwa Danish, Dana Marafi, Tarek M Kamal, Laila Bastaki, Muna Al Saffar, Edward Yang, Miao He, Christopher A Walsh, Ganeshwaran H Mochida, Hudson H Freeze.

Congenital disorders of glycosylation (CDG) are a phenotypically diverse group of genetic conditions arising from pathogenic variants in various glycosylation pathways. The most prevalent are N-glycosylation disorders. Here we present clinical and biochemical data on two siblings with a neurodevelopmental disorder and a pathogenic homozygous nonsense variant in Ribophorin I (RPN1), an essential component of the oligosaccharyltransferase (OST) complex. Both affected individuals showed a classical type I serum transferrin profile, while lymphoblasts revealed the variant resulted in a truncated RPN1 protein with reduced levels. The protein stability of other essential OST complex components, including STT3 Oligosaccharyltransferase Complex Catalytic Subunit A (STT3A), Ribophorin II (RPN2), and Dolichyl-Diphosphooligosaccharide (DDOST), was also significantly reduced. Structural modeling of both OST-A and OST-B complexes shows the RPN1 truncation eliminates a C-terminal four-helix bundle, which interacts with the translating ribosome. This interaction is necessary and specific for the co-translational activity of the OST-A complex. Supporting this observation, hypoglycosylation of an OST-A specific substrate protein was observed, while OST-B specific substrates were unaffected. These data convey that a rare loss of function RPN1 variant causes an autosomal recessive CDG characterized by neurodevelopmental deficits.

DOI: https://doi.org/10.1016/j.xhgg.2026.100604

Front Pediatr. 2026 ;14 1780997

Early neonatal diagnosis of SSR4-related congenital disorder of glycosylation with severe congenital heart defects: a case report and systematic review.

Lingxia Zhao, Lingkong Zeng, Minghui Yi, Wenhao Yuan.

Background: Congenital disorders of glycosylation type Iy (SSR4-CDG, CDG1Y) is an ultra-rare X-linked disorder caused by pathogenic variants in the SSR4 gene, encoding a subunit of the translocon-associated protein (TRAP) complex. While typically recognized for neurodevelopmental and facial features, its full neonatal spectrum, particularly regarding cardiac involvement, remains under-characterized.
Case presentation: We report a male neonate with the earliest postnatal diagnosis of SSR4-CDG (day of life 6). Prenatal testing revealed a novel, maternally inherited 65.63 kb hemizygous deletion at Xq28, encompassing SSR4 and partially deleting ABCD1. The neonatal presentation was dominated by multiple congenital heart defects (CHDs): Membranous ventricular septal defect, secundum atrial septal defect, persistent left superior vena cava, a narrow proximal left pulmonary artery, and coronary sinus dilation. Additional features included classic dysmorphism (wide mouth, deep-set eyes, micrognathia), severe hypotonia, feeding difficulties, and coagulopathy. Brain MRI revealed a thin corpus callosum.
Literature review & analysis: A systematic review of the literature, including reports published up to December 2025, identified 24 previously published cases. Pooled analysis incorporating the present patient (n = 28) confirmed that developmental delay/intellectual disability, hypotonia, characteristic facial features, and microcephaly were observed in 100% of cases. Congenital heart defects (CHDs) were present in 32.1% (9/28) of patients; however, the current case represents the first reported patient in whom severe CHDs constituted the predominant clinical manifestation. Detailed subgroup analyses further demonstrated that the frequency of clinical features varied across different age groups, indicating age-dependent phenotypic expression. All analyses were descriptive in nature, and no formal meta-analysis was performed due to the limited number of reported cases and heterogeneity in clinical data.
Conclusions: This case expands the neonatal phenotype of SSR4-CDG and highlights that, in some patients, severe congenital heart defects may represent an early and clinically significant manifestation. However, based on currently available evidence, cardiac anomalies remain an uncommon feature of the disorder. Prompt genetic evaluation should be considered in affected male neonates with syndromic features.

Keywords: CDG1Y; SSR4-CDG; TRAP complex; congenital disorders of glycosylation; congenital heart defects; contiguous gene deletion; neonatal diagnosis; x-linked disorder

DOI: https://doi.org/10.3389/fped.2026.1780997

Mol Genet Genomic Med. 2026 Apr;14(4): e70215

Novel Compound Heterozygous Variants in the COG5 Gene Causing Fetal Hydrops and Skeletal Dysplasia.

Qi Yang, Wei He, Qiang Zhang, Sheng Yi, Xunzhao Zhou, Linlin Wang, Shang Yi, Zailong Qin, Jingsi Luo.

INTRODUCTION: Congenital Disorders of Glycosylation (CDG) are a complex and highly heterogeneous group of rare metabolic disorders characterized by defects in enzymes and transporter proteins crucial for glycosylation pathways, including N-linked, O-linked, and glycolipid glycosylation. To date, over 160 distinct subtypes have been identified. CDG are characterized by significant clinical heterogeneity, which presents substantial challenges for diagnosis, especially in the prenatal setting. While prenatal ultrasound serves as a crucial tool for screening potential cases, the intricate nature of CDG often necessitates the use of advanced techniques such as whole-exome sequencing (WES) to obtain more precise molecular genetic evidence.
METHODS: To investigate the genetic causes of suspected CDG in a Chinese fetus, WES was performed. Subsequently, the detected variants and their origins were validated by Sanger sequencing and classified according to the guidelines of the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP).
RESULTS: A non-consanguineous couple had previously experienced fetal hydrops with skeletal dysplasia during midpregnancy. In their subsequent pregnancy, second-trimester ultrasonography again revealed fetal hydrops, a previously unreported complication. Fetal WES revealed two novel heterozygous variants in the COG5 gene (NM_006348.5), namely c.1972del(p.Val658Serfs*23) and c.2168_2168+4delinsCATAAAA. Sanger sequencing confirmed that the c.1972del(p.Val658Serfs*23) variant was paternally inherited, while the c.2168_2168+4delinsCATAAAA variant was maternal inherited. Both variants were classified as likely pathogenic according to the ACMG/AMP guidelines.
CONCLUSIONS: This study further expands the phenotypic and mutational spectrum of the COG5 gene, enhancing our understanding of COG5-CDG. Clinically, intellectual disability, developmental delay, brain abnormalities, skeletal deformities, microcephaly, short stature, vision abnormalities, and hepatic lesions are crucial diagnostic criteria for COG5-CDG. Other variable phenotypes of COG5-CDG can provide supporting information for prenatal diagnosis. The combined application of prenatal ultrasound and WES enables a more comprehensive and precise diagnosis of COG5-CDG, which will facilitate the implementation of early intervention and treatment.

Keywords: COG5 ; COG5‐CDG; novel variant; prenatal ultrasound; whole‐exome sequencing

DOI: https://doi.org/10.1002/mgg3.70215

Exp Mol Med. 2026 Apr 10.

Defective autophagy in GNE myopathy is rescued by inhibition of noncanonical Akt-mTORC1 activation across multiple isogenic models.

Dong-Woo Kim, Eun-Ji Kwon, Hyuk Kwon, Jumee Kim, Hyuk-Jin Cha.

GNE myopathy is a recessive autosomal disease caused by mutations in glucosamine (UDP-N-acetyl)-2-epimerase/N-acetylmannosamine kinase (GNE), characterized by impaired sialic acid biosynthesis and the formation of rimmed vacuoles. Similar to other autophagic vacuolar myopathies, defective autophagy has been implicated in disease pathogenesis; however, the underlying molecular mechanisms remain poorly understood. By performing transcriptome analysis on two independent GNE myoblast models derived from human pluripotent stem cells, we identified multiple autophagy-related gene sets as pathogenic signatures of GNE myopathy. These predictions were biochemically validated using Gne-knockout C2C12 myoblasts. Mechanistically, our data reveal that aberrant activation of the noncanonical AKT-mTORC1 pathway-driven by excessive extracellular matrix production-induces inhibitory phosphorylation of ULK1, thereby suppressing autophagy initiation. To identify therapeutic targets, we performed a transcriptome-based drug screen using gene signature reversal, which nominated copanlisib, an FDA-approved Pi3k inhibitor, as a promising candidate. Functional validation in human pluripotent stem cell-derived neuromuscular organoids demonstrated that copanlisib reactivates autophagy via restoration of ULK1 activity. Together, our findings uncover a mechanistic link between extracellular matrix dysregulation and impaired autophagy in GNE myopathy and highlight copanlisib as a potential therapeutic strategy.

DOI: https://doi.org/10.1038/s12276-026-01701-7