GLDN – Lethal Congenital Contracture Syndrome 11

Lethal congenital contracture syndrome 11 (LCCS11) is an autosomal recessive form of fetal akinesia deformation sequence characterized by fixed limb joints, intrauterine growth restriction, and high neonatal mortality. GLDN (Gene Symbol) encodes an olfactomedin-containing protein critical for node-of-Ranvier formation in peripheral nerves. Affected fetuses and infants present hydrops, distal arthrogryposis, pulmonary hypoplasia, retrognathia, and polyhydramnios.

Genetic evidence for GLDN in LCCS11 includes 13 probands (PMID:35806855; PMID:35740734; PMID:39713852; PMID:28726266) from nine unrelated families. Biallelic variants, including homozygous missense and compound heterozygous missense and truncating alleles, segregate with disease under autosomal recessive inheritance.

Segregation analysis demonstrates two Canadian Inuit families with a homozygous founder variant c.82G>C (p.Ala28Pro) in five affected individuals (PMID:39713852) and compound heterozygous segregation in four additional families (PMID:28726266).

The variant spectrum comprises missense substitutions (e.g., c.82G>C (p.Ala28Pro), c.1494G>T (p.Leu498Phe), c.1093C>T (p.Leu365Phe)), nonsense alleles (c.1305G>A (p.Trp435Ter), c.1240C>T (p.Arg414Ter)), and other loss-of-function changes.

Functional assays in HEK293 cells reveal that the p.Leu365Phe variant impairs gliomedin secretion and nodal assembly, and complementation studies of four additional patient alleles confirm disrupted protein trafficking and function, supporting a loss-of-function mechanism (PMID:32812332).

Clinical outcomes range from prenatal demise to survival into adolescence; survivors present progressive respiratory insufficiency and diaphragmatic hypomotility (PMID:35740734), underscoring variable expressivity and the necessity of early genetic diagnosis for management and counseling.

Integration of genetic and functional data affords a strong association of GLDN with LCCS11. Genetic testing for biallelic GLDN variants enables confirmation of diagnosis, informs prognosis, and guides perinatal care and long-term respiratory support. Key take-home: GLDN biallelic loss-of-function underlies LCCS11 with core neuromuscular and respiratory phenotypes amenable to early intervention.

References

• Journal of clinical medicine • 2022 • Lethal Congenital Contracture Syndrome 11: A Case Report and Literature Review. PMID:35806855
• Children (Basel, Switzerland) • 2022 • Progressive Respiratory Insufficiency in a Teenager with Diaphragmatic Hypomotility Due to a Novel Combination of Gliomedin Gene Variants. PMID:35740734
• Human mutation • 2017 • Survival among children with "Lethal" congenital contracture syndrome 11 caused by novel mutations in the gliomedin gene (GLDN). PMID:28726266
• American journal of medical genetics. Part A • 2020 • The latest FADS: Functional analysis of GLDN patient variants and classification of GLDN-associated AMC as a type of viable fetal akinesia deformation sequence. PMID:32812332
• Unknown Journal • n.d. • Title Not Provided. PMID:39713852

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