Homozygous variants in AMPD2 and COL11A1 lead to a complex phenotype of pontocerebellar hypoplasia type 9 and Stickler syndrome type 2

Am J Med Genet A. 2020 Mar;182(3):557-560. doi: 10.1002/ajmg.a.61452. Epub 2019 Dec 12.


Pontocerebellar hypoplasia type 9 (PCH9) is an autosomal recessive neurodevelopmental disorder caused by pathogenic variants in the AMPD2 gene. We evaluated the son of a consanguineous couple who presented with profound hypotonia and global developmental delay. Other features included sensorineural hearing loss, asymmetric astigmatism, and high myopia. Clinical whole-exome sequence analysis identified a homozygous missense variant in AMPD2 (NM_001257360.1:c.2201C > T, p.[Pro734Leu]) that has not been previously reported. Given the strong phenotypic overlap with PCH9, including the identification of the typical "Figure 8" appearance of the brainstem on neuroimaging, we suspect this variant was causative of the neurodevelopmental disability in this individual. An additional homozygous nonsense variant in COL11A1 (NM_001854.4:c.1168G > T, p.[Glu390Ter]) was identified. Variants in this alternatively spliced region of COL11A1 have been identified to cause an autosomal recessive form of Stickler syndrome type 2 characterized by sensorineural hearing loss and eye abnormalities, but without musculoskeletal abnormalities. The COL11A1 variant likely also contributed to the individual's phenotype, suggesting two potentially relevant genetic findings. This challenging case highlights the importance of detailed phenotypic characterization when interpreting whole exome data.

Keywords: AMPD2; COL11A1; PCH9; Pontocerebellar hypoplasia; Stickler syndrome type 2.

Publication types

  • Case Reports

MeSH terms

  • AMP Deaminase / genetics*
  • Cerebellar Diseases / diagnosis
  • Cerebellar Diseases / diagnostic imaging
  • Cerebellar Diseases / genetics*
  • Cerebellar Diseases / pathology
  • Child, Preschool
  • Collagen Type XI / deficiency*
  • Collagen Type XI / genetics
  • Connective Tissue Diseases / diagnosis
  • Connective Tissue Diseases / diagnostic imaging
  • Connective Tissue Diseases / genetics*
  • Connective Tissue Diseases / pathology
  • Exome / genetics
  • Female
  • Homozygote
  • Humans
  • Infant
  • Magnetic Resonance Imaging
  • Male
  • Mutation / genetics
  • Pedigree
  • Phenotype
  • Vitreous Detachment / diagnosis
  • Vitreous Detachment / diagnostic imaging
  • Vitreous Detachment / genetics*
  • Vitreous Detachment / pathology


  • COL11A1 protein, human
  • Collagen Type XI
  • AMP Deaminase
  • AMPD2 protein, human

Supplementary concepts

  • Pontocerebellar Hypoplasia
  • Stickler syndrome, type 2