The first case of antenatal presentation in COG8‐congenital disorder of glycosylation with a novel splice site mutation and an extended phenotype

Abstract

Congenital disorders of glycosylation (CDG) are an extremely rapidly growing and phenotypically versatile group of disorders. Conserved oligomeric Golgi (COG) complexes are hetero-octameric proteins involved in retrograde trafficking within the Golgi. Seven of its eight subunits have a causal role in CDG. To date, only three cases of COG8-CDG have been published but none in the antenatal period. We present the first case of antenatally diagnosed COG8-CDG with facial dysmorphism and additional features such as Dandy-Walker malformation and arthrogryposis multiplex congenita, thus expanding the phenotype of this rare disorder. Trio whole exome sequencing revealed a novel homozygous variant in COG8, which creates a new splice site in exon 5 and protein truncation after 12 amino acids downstream to the newly generated splice site. As the mutations of the previous three patients were also identified in exon 5, it is likely to be a potential mutational hotspot in COG8. An association between antenatally increased nuchal translucency and COG8-CDG is also established, which would alert clinicians to its diagnosis early in gestation.It remains to be seen if this observation can be extended to other COG-CDGs. K E Y W O R D Santenatal presentation, arthrogryposis multiplex congenita, COG8-CDG, Dandy-Walker malformation, increased NT, mutational hotspot

Golgi inCOGnito: From vesicle tethering to human disease

“…This patient exhibited milder psychomotor retardation without a seizure history or severe ocular symptoms, unlike other COG8-CDG patients. Arora et al 2019 [ 112 ] reported a patient who was severely affected compared to the 3 earlier COG8-CDG patients. Antenatal conditions included increased nuchal translucency, arthrogryposis multiplex congenita, Dandy-Walker malformation and fetal growth restrictions.…”

Maintaining order: COG complex controls Golgi trafficking, processing, and sorting

“…N-glycan mass spectrometry (MS) analysis confirmed hyposialylation of N-glycans, similar to CHO-COG mutants and COG-CDG patients (discussed in the next section). Fly COG mutants also displayed increased high-mannose, paucimannose, and Humans, COG4-CDG COG4 (R729W), COG4 (G516R) Cells: reduction in COG3 (50%), COG2 (40%), COG1 (25%), and COG5 (40%) protein levels, COG complex formation seemed to be unaffected, mild Golgi dysfunction (compared to COG7 or COG8-CDG), Golgi dilatation and fragmentationPatients: Saul-Wilson syndrome, a rare form of primordial dwarfism with characteristic facial and radiographic features [102,115] Humans, COG5-CDG COG5 (homozygous intronic substitution (c.1669-15T>C) leading to exon skipping) Cells: undersialylation of N-and O-glycansPatients: moderate psychomotor retardation with language delay, truncal ataxia and slight hypotonia [110,166,174,175] Humans, COG6-CDG COG6 (G549V) Cells: reduction in STX6 levels, glycosylation defects including reduced sialyation of O-glycans; decreased activity of B4GALT1 but normal import of UDP-galactose into the Golgi, reduced protein levels of COG5 (55%), COG6 (21%), and COG7 (62%), degradation of mRNA encoding COG6, formation of the COG complex affectedPatients: microcephaly, chronic inflammatory bowel disease, micronodular liver cirrhosis, severe neurologic disease characterized by vitamin K deficiency, vomiting, intractable focal seizures, intracranial bleedings and fatal outcome in early infancy [176][177][178][179] Humans, COG7-CDG COG7 (intronic splice site mutation (c.169+4A>C)) Cells: disruption of multiple N-and O-glycosylation pathways, completely destabilized COG complexPatients: growth retardation, microcephaly, hypotonia, adducted thumbs, feeding problems, failure to thrive, cardiac anomalies, wrinkled skin and episodes of extreme hyperthermia, skeletal anomalies and a mild liver involvement [96,101,173,180] Humans, COG8-CDG COG8 Cells: deficient in sialylation of both N-and O-glycans, slower brefeldin A induced disruption of the Golgi matrix, reduction in COG1, COG5, COG6, and COG7 protein levels but not COG2, COG3 and COG4, COG5, COG6, and COG7 were also mislocalizedPatients: cerebellar atrophy, Elevated blood creatine phosphokinase, Alternating esotropia, psychomotor retardation, failure to thrive, intolerance to wheat and dairy products, lack of bowel or bladder control, dry skin with keratosis pilaris, mild contractures of the lower extremities [99,100,103,107,108] Humans, TMED6-COG8 translocation…”

“…In humans, COG mutations result in a COG specific, type‐II Congenital Disorders of Glycosylation (or a COG‐CDG for short) . Mutations in seven of the eight COG subunits (COG3 being the exception) have been identified as CDG causing . CDGs are a very heterogeneous group of disorders, caused by a wide variety of altered gene products, and can result in defects in N‐ glycosylation alone or N‐, O‐, and lipid‐linked glycosylation .…”

In case you missed it: The Prenatal Diagnosis editors bring you the most significant advances of 2019

“…34 Additional abnormalities were noted at 28 weeks and included moderate unilateral ventriculomegaly (14 mm), Dandy-Walker malformation, and multiple joint contractures (later shown to be arthrogryposis multiplex congenita). 34 The fetus 35 As new fetal phenotypes are reported in association with a variety of novel mutations, we need to ensure that enough evidence exists before causally linking a specific variant with specific fetal anomalies. Such evidence usually stems from functional and animal model studies as well as the enrichment of the variant in unrelated fetuses with concordant phenotypes and the absence of the variant in normal individuals.…”

“…In some instances, the fetus may “grow into the phenotype” during the pregnancy as reported by Arora et al who described a fetus with an NT that increased from 2.9 mm at 12 weeks to 7 mm at 17 weeks . Additional abnormalities were noted at 28 weeks and included moderate unilateral ventriculomegaly (14 mm), Dandy‐Walker malformation, and multiple joint contractures (later shown to be arthrogryposis multiplex congenita) . The fetus expired 2 days post birth, and WES revealed an inherited homozygous novel splice site variant in COG8 , a gene associated with a congenital disorder of glycosylation.…”