COG6-related prenatal phenotype (CDG2L): Clinico-pathological report and review of the literature

Abstract

Background: CDG2L (MIM#614576) is an autosomal recessive multisystemic disorder due to variants in COG6 gene. Postnatal phenotypes are now well described, while prenatal presentations remain poorly investigated. Only 8 of the 28 published patients have had prenatal ultrasound anomalies reported and no one post-mortem investigation.

Methods: We used whole-exome sequencing in a consanguineous Turkish family with four siblings presenting with Pierre Robin sequence, arthrogryposis, heart malformation, splenomegaly, hydrocephaly, corpus callosum dysgenesis, brainstem, and cerebellar hypoplasia.

Results: We identified a novel homozygous pathogenic variant in exon 9 of COG6 (NM_020751.2): c.821del, p.(Arg274Lysfs*32). In this family, our post-mortem study led us to describe further the prenatal phenotype of CDG2L. In addition, it permits correlating the most relevant anomalies to a maldevelopmental cascade due to a neurodegenerative process of metabolic origin, affecting the entire central nervous system including the spinal cord.

Conclusion: In this context of recurrence of multisystemic disease diagnosed antenatally, exome sequencing is powerful to give a precise diagnosis and allows proposing a molecular prenatal diagnosis at the following pregnancy.

Keywords: arthrogryposis; congenital disorders of glycosylation; corpus callosum; exome sequencing; prenatal ultrasound.

FIGURE 1

Obstetrical ultrasound images of fetus II.3 at 34 WG. (a) Sagittal view of hypoplastic corpus callosum, white arrow = small and thin corpus callosum; (b) Coronal view of Moose head sign: ascension of lateral ventricles; (c) Cardiac four chamber view showing right ventricle hypoplasia (white arrow). (d) External genitalia: small penis, scrotum with no testis inside.

FIGURE 2

Obstetrical ultrasound images of fetus II.4. (a) Elevated nuchal translucency at first trimester examination; (b) 22 WG, sagittal view of the fetus back showing rachidian angulation, a depression in the lumbar rachis can be noted; (c) 22 WG, abnormal cerebellum with dedifferenciated echogenicity due to the absence of the hyperechogenic ring usually delimiting the cerebellum, no vermis is seen; (d) Normal cerebellum of a 22 WG fetus, note the difference of echogenicity with fetus II.4 and the presence of the vermis in the middle, thick arrow = cerebellum, thin arrow = vermis; (e) 22 WG, sagittal view of face and brain showing retrognathism and hypoplastic corpus callosum, the corpus callosum seems to be normal posteriorly but very thin anteriorly, no vermis is seen; (f) Normal sagittal view of a 22 WG fetus, thick arrow = corpus callosum, thin arrow = vermis.

FIGURE 3

Clinicopathological and neuropathological findings of fetus II.4. (a) Large and slightly inverted nipples, more pronounced on the left nipple. (b) External cardiac examination: ventriculo‐arterial asymmetry with a small right ventricle (white circle) leading to interventricular sulcus pushed on the right; (c) Histological examination of quadriceps muscle: fibers with regular size in an abundant and loose stroma. (d) External appearance of the cerebral hemispheres with fronto‐parietal lobes filled with nodules, corresponding to (e) Neuroglial ectopias into the arachnoid space; (f) Dysmorphic corpus callosum, thick on the anterior part; (g) Asymmetric lateral ventricles; (h) Hypoplastic vermis (white circle), collapsed fourth ventricle; (i) Poor foliation of the cerebellum.

FIGURE 4

Obstetrical ultrasound images of fetus II.4. (a) Increased NT 8.3 mm. (b) Generalized edema. (c) One heart great vessel.