Aradhana Dwivedi Department of Medical Genetics, Sanjay Gandhi Post graduate Institute of Medical Sciences, Lucknow, India Email:aradhanakd@gmail.com
1 Mystery of LCC (leukoencephalopathy, intracranial calcifications and cysts)- SNORDed out. . . (Jenkinson et al.,
2016)
Monogenic causes of ribosomal dysfunction can confer a remarkable degree of specificity in terms of human disease
phenotype. Box C/D small nucleolar RNAs (snoRNAs) are evolutionarily conserved non-protein-coding RNAs involved in
ribosome biogenesis. Biallelic mutations in the gene SNORD118, encoding the box C/D snoRNA U8, cause the cerebral
microangiopathic leukoencephalopathy with calcifications and cysts (LCC), presenting at any age from early childhood to
late adulthood. These mutations affect U8 expression, processing and protein-binding and thus implicate U8 as essential
in cerebral vascular homeostasis.
2 Want “Mr Perfect genome” - Barcode it (Peters et al., 2014)
Next generation sequencing (NGS) technologies, primarily based on massively parallel sequencing, have
touched and radically changed almost all aspects of research worldwide. Despite all of this progress, the
current state-of-the-art in sequence technology is far from generating a “perfect genome” sequence and
much remains to be understood in the biology of human and other organisms’ genomes. In this paper, the
authors outline why the “perfect genome” in humans is important, what is lacking from current human whole
genome sequences, and a potential strategy for achieving the “perfect genome” in a cost effective manner.
The “Perfect genome” solution employs advanced massively parallel DNA sequencing of “co-barcoded”
reads from long genomic DNA molecules, and efficient de novo assembly empowered by these barcoded
reads.
3 Whole genome sequencing in pediatric practice- Now, next or later (Stavopoulous et al., 2016)
The recommended first-tier clinical investigation for identifying the etiology of congenital malformations and
neurodevelopmental disorders is chromosome microarray analysis (CMA) for copy-number variations (CNVs), often
followed by gene(s)-specific sequencing to search for smaller insertion–deletions (indels) and single-nucleotide variant
(SNV) mutations. In this prospective study the authors utilized whole genome sequencing (WGS) and
comprehensive medical annotation to assess 100 patients referred to a Pediatric Genetics service and compared the
diagnostic yield versus standard genetic testing. WGS identified genetic variants meeting clinical diagnostic
criteria in 34% of cases, representing a fourfold increase in the diagnostic rate over CMA alone and more
than twofold increase in CMA plus targeted gene sequencing. WGS identified all rare clinically significant
CNVs that were detected by CMA. Clinical implementation of WGS as a primary test will provide a higher
diagnostic yield than conventional genetic testing and potentially reduce the time required to reach a genetic
diagnosis.
4 Holoprosencephaly- Not so simple (Mouden et al., 2016)
Holoprosencephaly (HPE) is the most common congenital cerebral malformation, characterized by impaired forebrain
cleavage and midline facial anomalies. Heterozygous mutations in 14 genes have been associated with HPE and are often
inherited from an unaffected parent, underlying complex genetic bases. HPE may result from a combination of multiple
genetic events. In this study the authors have used whole exome sequencing and targeted high-throughput sequencing
approaches to identify mutations in HPE subjects. They reported two HPE families in which two mutations are
implicated in the disease. In the first family with two fetuses with alobar and semi-lobar HPE, mutations were found in
two genes involved in HPE, SHH and DISP1, inherited respectively from the father and the mother. The second reported
case was a family with a 9-year-old girl presenting with lobar HPE, who was found to harbour two compound
heterozygous mutations in DISP1. Together, these cases of digenic inheritance and autosomal recessive HPE
suggest that in some families, several genetic events are necessary to cause HPE. This study highlights the
complexity of HPE inheritance and has to be taken into account by clinicians to improve genetic counseling for
HPE.
References
1. Jenkinson EM, et al. Mutations in SNORD118 cause the cerebral microangiopathy leukoencephalopathy
with calcifications and cysts. Nat Genet 2016; 48: 1185-1192.
2. Peters BA, et al. Co-barcoded sequence reads from long DNA fragments: a cost-effective solution for “perfect
genome” sequencing. Front Genet 2014; 5: 466.
3. Stavropoulos DJ, et al. Whole-genome sequencing expands diagnostic utility and improves clinical
management in paediatric medicine. Genomic Medicine 2016. doi:10.1038/npjgenmed.2015.12
4. Mouden C, et al. Complex mode of inheritance in holoprosencephaly revealed by whole exome sequencing.
Clin Genet 2016; 89: 659-668.