A large homozygous deletion in the SAMHD1 gene causes atypical Aicardi-Goutiéres syndrome associated with mtDNA deletions

Abstract

Aicardi-Goutiéres syndrome (AGS) is a genetic neurodegenerative disorder with clinical symptoms mimicking a congenital viral infection. Five causative genes have been described: three prime repair exonuclease1 (TREX1), ribonucleases H2A, B and C, and most recently SAM domain and HD domain 1 (SAMHD1). We performed a detailed clinical and molecular characterization of a family with autosomal recessive neurodegenerative disorder showing white matter destruction and calcifications, presenting in utero and associated with multiple mtDNA deletions. A muscle biopsy was normal and did not show any evidence of respiratory chain dysfunction. Southern blot analysis of tissue from a living child and affected fetuses demonstrated multiple mtDNA deletions. Molecular analysis of genes involved in mtDNA synthesis and maintenance (POLGα, POLGβ, Twinkle, ANT1, TK2, SUCLA1 and DGOUK) revealed normal sequences. Sequencing of TREX1 and ribonucleases H2A, B and C failed to reveal any mutations. Whole-genome homozygosity mapping revealed a candidate region containing the SAMHD1 gene. Sequencing of the gene in the affected child and two affected fetuses revealed a large deletion (9 kb), spanning the promoter, exon1 and intron 1. The parents were found to be heterozygous for this deletion. The identification of a homozygous large deletion in the SAMHD1 gene causing atypical AGS with multiple mtDNA deletions may add information regarding the involvement of mitochondria in self-activation of innate immunity by cell intrinsic components.

Figure 1

(a) Axial T2-weighted image of the proband at age 2 months showing diffuse hyperintense changes in the deep white matter and the U-fibers associated with cortical atrophy. (b) Coronal T2-weighted image of the proband at age 2 months shows diffuse white matter changes and periventricular cysts, involving the head of the caudate bilaterally. (c) Fourth pregnancy. MRI-coronal HASTE at 33 weeks of gestation showing cysts of the caudate nuclei and increased signal in the white matter of the temporal lobes. (d) Fourth pregnancy. US in the parasagittal transvaginal plane at 34 weeks 2 days showing dotted areas of increased echogenicity in the caudate and thalamus (arrow). (e) Parasagittal transvaginal plane at 34 weeks 2 days showing a hypoechogenic rim around the posterior horn of the lateral ventricle. (f) Fifth pregnancy. MRI-sagittal HASTE, 33 weeks of gestation of the fifth pregnancy. Cystic lesions of frontal white matter and caudate nucleus enlarged lateral ventricle. (g) Fifth pregnancy. US in the parasagittal view at 34 weeks 2 days showing an abnormally echogenic caudate (white arrow). (h) Fifth pregnancy. Coronal plane at 34 weeks 2 days showing dotted areas of increased echogenicity in the caudate (arrow). Note the irregular shape of the lateral ventricle on the same side.

Figure 2

Brain histology of aborted fetus (fourth pregnancy). H&E stain showing calcifications in the white matter surrounded by glial and microglial reaction.

Figure 3

(a) SAMHD1-deletion breakpoints. PCR primers across the deletion and a chromatogram demonstrating the sequence across the breakpoints. (b) PCR amplification of exon 1. (c) PCR amplification across the deletion breakpoints. M-100 bp ladder; 1: father; 2: mother; 3: proband, 4: CVS – 7th pregnancy; 5: fetus I; 6: fetus II; 7: normal; 8: normal; 9: blank. (d) Pedigree of the family with SAMHD1 genotypes. (e) Southern blot analysis of PvuII-digested DNA of the proband (1) and the two aborted fetuses (2) in various tissues.