Leukoencephalopathy with calcifications and cysts: Genetic and phenotypic spectrum

Abstract

Biallelic mutations in SNORD118, encoding the small nucleolar RNA U8, cause leukoencephalopathy with calcifications and cysts (LCC). Given the difficulty in interpreting the functional consequences of variants in nonprotein encoding genes, and the high allelic polymorphism across SNORD118 in controls, we set out to provide a description of the molecular pathology and clinical spectrum observed in a cohort of patients with LCC. We identified 64 affected individuals from 56 families. Age at presentation varied from 3 weeks to 67 years, with disease onset after age 40 years in eight patients. Ten patients had died. We recorded 44 distinct, likely pathogenic, variants in SNORD118. Fifty two of 56 probands were compound heterozygotes, with parental consanguinity reported in only three families. Forty nine of 56 probands were either heterozygous (46) or homozygous (three) for a mutation involving one of seven nucleotides that facilitate a novel intramolecular interaction between the 5′ end and 3′ extension of precursor‐U8. There was no obvious genotype–phenotype correlation to explain the marked variability in age at onset. Complementing recently published functional analyses in a zebrafish model, these data suggest that LCC most often occurs due to combinatorial severe and milder mutations, with the latter mostly affecting 3′ end processing of precursor‐U8.

Case report: Moderate therapeutic response to Bevacizumab in late-onset Labrune syndrome

“…Genetic analysis of our patient confirmed compound heterozygous SNORD118 mutations, n.3C>T and n.24C>T. The site of n.3C>T mutation had been reported in 4 patients with various ages of onset, from 2 years to 30 years ( 5 , 6 ), indicating that site of genetic mutation did not correlate with the age of presentation. While n.24C>T mutation had been reported in an 11-year-old onset male ( 5 ) who presented with symptoms of raised intracranial pressure. Both mutations of n.3C>T and n.24C>T were located at the 5' end of pre-U8, which might be associated with impaired U8 processing ( 5 ).…”

“…While n.24C>T mutation had been reported in an 11-year-old onset male ( 5 ) who presented with symptoms of raised intracranial pressure. Both mutations of n.3C>T and n.24C>T were located at the 5' end of pre-U8, which might be associated with impaired U8 processing ( 5 ). Taken together, no evidence showed an obvious genotype-phenotype correlation in LS.…”

Case Report: Clinical Features of Childhood Leukoencephalopathy With Cerebral Calcifications and Cysts Due to SNORD118 Variants

“…The onset age of LCC patients with a determined genotype had been reported ranging from 3 weeks to 67 years old. The patient who had the earliest onset age was a female reported by Crow et al (22), presenting seizures at the disease onset. In this manuscript, our case had his first seizure at 10 days after birth, which is earlier than her and all other reported cases until now.…”

“…It seemed that the combination of these two variants presumably would not result in disease, as homozygous mutations were found in gnomAD (Table 1). It was predicted that such hypomorphic mutant homozygotes would result in the reduction of U8 activity to a level, which is compatible with initially normal development, but insufficient to maintain cellular homeostasis long-term (22). More cases with combination of two "mild" alleles or hypomorphic mutant homozygotes were needed for a better understanding of the molecular pathology of LCC.…”

Small RNA sequencing reveals snoRNAs and piRNA-019825 as novel players in diabetic kidney disease

“…These snoRNAs are encoded within the TMEM107 gene on chromosome 17p13.1, where U8 is transcribed from SNORD118 locus. Mutations in SNORD118 cause a rare genetic cerebral microangiopathy called leukoencephalopathy with brain calcifications and cysts (LCC; also known as Labrune syndrome) (39). However, based on current evidence this a strictly neurological disease with no evidence for involvement of other tissues or the kidneys.…”