Within the past 5 years, new techniques for comprehensive genetic testing, such as
whole-exome sequencing, have been introduced into clinical practice. Success rates
vary, greatly depending on stringent selection criteria for the cohorts studied. Illustrated
by examples from the heterogeneous group of hypomyelinating disorders, we show how
these novel techniques changed proportion of solved cases, knowledge of clinical variability
and insights into pathogenesis. We also demonstrate how to deal with seemingly negative
results encountered in two disorders, hypomyelination of early myelinating structures
(HEMS) and hypomyelination with spondylometaphyseal dysplasia (H-SMD), defying for
some time all attempts of finding the responsible gene.
