TY - JOUR

T1 - Role of reverse phenotyping in interpretation of next generation sequencing data and a review of INPP5E related disorders

AU - De Goede, Christian

AU - Yue, Wyatt W.

AU - Yan, Guanhua

AU - Ariyaratnam, Shyamala

AU - Chandler, Kate E.

AU - Downes, Laura

AU - Khan, Nasaim

AU - Mohan, Meyyammai

AU - Lowe, Martin

AU - Banka, Siddharth

PY - 2016/3

Y1 - 2016/3

N2 - IntroductionNext Generation Sequencing (NGS) is a useful tool in diagnosis of rare disorders but the interpretation of data can be challenging in clinical settings. We present results of extended studies on a family of multiple members with global developmental delay and learning disability, where another research group postulated the underlying cause to be a homozygous RABL6 missense variant.Methods and resultsUsing data from the Exome Variant Server, we show that missense RABL6 variants are unlikely to cause early onset rare developmental disorder. Protein structural analysis, cellular functional studies and reverse phenotyping proved that the condition in this family is due to a homozygous INPP5E mutation.An in-depth review of mutational and phenotypic spectrum associated with INPP5E demonstrated that mutations in this gene lead to a range of cilliopathy-phenotypes.DiscussionWe use this study as an example to demonstrate the importance of careful clinical evaluation of multiple family members, reverse phenotyping, considering the unknown phenotypic variability of rare diseases, utilizing publically available genomic databases and conducting appropriate bioinformatics and functional studies while interpreting results from NGS in uncertain cases. We emphasize that interpretation of NGS data is an iterative process and its dynamic nature should be explained to patients and families.Our study shows that developmental delay, intellectual disability, hypotonia and ocular motor apraxia are common in INPP5E-related disorders and considerable intra-familial phenotypic variability is possible. We have compiled the INPP5E mutational spectrum and provided novel insights into their molecular mechanisms.

AB - IntroductionNext Generation Sequencing (NGS) is a useful tool in diagnosis of rare disorders but the interpretation of data can be challenging in clinical settings. We present results of extended studies on a family of multiple members with global developmental delay and learning disability, where another research group postulated the underlying cause to be a homozygous RABL6 missense variant.Methods and resultsUsing data from the Exome Variant Server, we show that missense RABL6 variants are unlikely to cause early onset rare developmental disorder. Protein structural analysis, cellular functional studies and reverse phenotyping proved that the condition in this family is due to a homozygous INPP5E mutation.An in-depth review of mutational and phenotypic spectrum associated with INPP5E demonstrated that mutations in this gene lead to a range of cilliopathy-phenotypes.DiscussionWe use this study as an example to demonstrate the importance of careful clinical evaluation of multiple family members, reverse phenotyping, considering the unknown phenotypic variability of rare diseases, utilizing publically available genomic databases and conducting appropriate bioinformatics and functional studies while interpreting results from NGS in uncertain cases. We emphasize that interpretation of NGS data is an iterative process and its dynamic nature should be explained to patients and families.Our study shows that developmental delay, intellectual disability, hypotonia and ocular motor apraxia are common in INPP5E-related disorders and considerable intra-familial phenotypic variability is possible. We have compiled the INPP5E mutational spectrum and provided novel insights into their molecular mechanisms.

KW - Reverse phenotyping

KW - Next generation sequencing

KW - INPP5E

KW - Joubert syndrome

KW - MORM syndrome

KW - RABL6

KW - C9orf86

U2 - 10.1016/j.ejpn.2015.11.012

DO - 10.1016/j.ejpn.2015.11.012

M3 - Journal article

VL - 20

SP - 286

EP - 295

JO - European Journal of Paediatric Neurology

JF - European Journal of Paediatric Neurology

SN - 1090-3798

IS - 2

ER -