Advantages and pitfalls of an extended gene panel for investigating complex neurometabolic phenotypes.
Neurometabolic disorders are markedly heterogeneous, both clinically and genetically, and are characterized by variable neurological dysfunction accompanied by suggestive neuroimaging or biochemical abnormalities. Despite early specialist input, delays in diagnosis and appropriate treatment initiation are common. Next-generation sequencing approaches still have limitations but are already enabling earlier and more efficient diagnoses in these patients. We designed a gene panel targeting 614 genes causing inborn errors of metabolism and tested its diagnostic efficacy in a paediatric cohort of 30 undiagnosed patients presenting with variable neurometabolic phenotypes. Genetic defects that could, at least partially, explain observed phenotypes were identified in 53% of cases. Where biochemical abnormalities pointing towards a particular gene defect were present, our panel identified diagnoses in 89% of patients. Phenotypes attributable to defects in more than one gene were seen in 13% of cases. The ability of in silico tools, including structure-guided prediction programmes to characterize novel missense variants were also interrogated. Our study expands the genetic, clinical and biochemical phenotypes of well-characterized (POMGNT1, TPP1) and recently identified disorders (PGAP2, ACSF3, SERAC1, AFG3L2, DPYS). Overall, our panel was accurate and efficient, demonstrating good potential for applying similar approaches to clinically and biochemically diverse neurometabolic disease cohorts.
Genetics and Genomics Medicine Programme, UCL Institute of Child Health, London, UK.
Emma S
ES
Reid
Genetics and Genomics Medicine Programme, UCL Institute of Child Health, London, UK.|Neurology Department, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
Apostolos
A
Papandreou
North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
Suzanne
S
Drury
North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
Christopher
C
Boustred
Structural Genomics Consortium, University of Oxford, Oxford, UK.
Wyatt W
WW
Yue
Genetics and Genomics Medicine Programme, UCL Institute of Child Health, London, UK.
Yehani
Y
Wedatilake
North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
Clare
C
Beesley
Histopathology Department, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.|Developmental Biology and Cancer Programme, UCL Institute of Child Health, London, UK.
Thomas S
TS
Jacques
Histopathology Department, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
Glenn
G
Anderson
Metabolic Medicine Department, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
Lara
L
Abulhoul
Metabolic Medicine Department, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
Alex
A
Broomfield
Metabolic Medicine Department, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
Maureen
M
Cleary
Genetics and Genomics Medicine Programme, UCL Institute of Child Health, London, UK.|Metabolic Medicine Department, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
Stephanie
S
Grunewald
Neurology Department, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
Sophia M
SM
Varadkar
North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
Nick
N
Lench
Genetics and Genomics Medicine Programme, UCL Institute of Child Health, London, UK.|Metabolic Medicine Department, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
Shamima
S
Rahman
Genetics and Genomics Medicine Programme, UCL Institute of Child Health, London, UK.|Metabolic Medicine Department, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
Paul
P
Gissen
Genetics and Genomics Medicine Programme, UCL Institute of Child Health, London, UK.
Peter T
PT
Clayton
Genetics and Genomics Medicine Programme, UCL Institute of Child Health, London, UK.
Philippa B
PB
Mills
D000293:Adolescent; D001928:Brain Diseases, Metabolic / Q000000981:diagnostic imaging / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D005838:Genotype; D006801:Humans; D021621:Imaging, Three-Dimensional; D007223:Infant; D008279:Magnetic Resonance Imaging; D008297:Male; D008661:Metabolism, Inborn Errors / Q000000981:diagnostic imaging / Q000235:genetics*; D010641:Phenotype; D000091346:Tripeptidyl-Peptidase 1; D055815:Young Adult
gene panel; heterogeneity; inborn errors of metabolism; neurometabolic disorders; next-generation sequencing