An example of the utility of genomic analysis for fast and accurate clinical diagnosis of complex rare phenotypes.
We describe molecular diagnosis in a complex consanguineous family: four offspring presented with combinations of three distinctive phenotypes; non-syndromic hearing loss (NSHL), an unusual skeletal phenotype comprising multiple fractures, cranial abnormalities and diaphyseal expansion, and significant developmental delay with microcephaly. We performed Chromosomal Microarray Analysis on the offspring with either the skeletal or developmental delay phenotypes, and linkage analysis and whole exome sequencing (WES) on all four children, parents and maternal aunt.



Chromosomal microarray and FISH analysis identified a de novo unbalanced translocation as a cause of the microcephaly and severe developmental delay. WES identified a NSHL-causing splice variant in an autosomal recessive deafness gene PDZD7 which resided in a linkage region and affected three of the children. In the two children diagnosed with an unusual skeletal phenotype, WES eventually disclosed a heterozygous COL1A1 variant which affects C-propetide cleavage site of COL1. The variant was inherited from an apparently unaffected mosaic father in an autosomal dominant fashion. After the discovery of the COL1A1 variant, the skeletal phenotype was diagnosed as a high bone mass form of osteogenesis imperfecta.



Next generation sequencing offers an unbiased approach to molecular genetic diagnosis in highly heterogeneous and poorly characterised disorders and enables early diagnosis as well as detection of mosaicism.
Genetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, 30 Guilford Street, London, WC1N 1EH, UK.
Polona
P
Le Quesne Stabej
Genetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, 30 Guilford Street, London, WC1N 1EH, UK.
Chela
C
James
Genetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, 30 Guilford Street, London, WC1N 1EH, UK.
Louise
L
Ocaka
Division of Medicine, UCL, London, UK.
Mehmet
M
Tekman
Department of Paediatric Metabolic Medicine, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
Stephanie
S
Grunewald
North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
Emma
E
Clement
Division of Medicine, UCL, London, UK.
Horia C
HC
Stanescu
Division of Medicine, UCL, London, UK.
Robert
R
Kleta
North East Thames Regional Genetics Laboratory, London, UK.
Deborah
D
Morrogh
Radiology Department, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
Alistair
A
Calder
Genetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, 30 Guilford Street, London, WC1N 1EH, UK.
Hywel J
HJ
Williams
Genetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, 30 Guilford Street, London, WC1N 1EH, UK. maria.bitner@ucl.ac.uk.
Maria
M
Bitner-Glindzicz
D002675:Child, Preschool; D003241:Consanguinity; D002658:Developmental Disabilities; D005786:Gene Expression Regulation; D023281:Genomics; D034381:Hearing Loss / Q000235:genetics*; D006801:Humans; D009154:Mutation; D035583:Rare Diseases / Q000235:genetics*; D035781:Siblings; D000073359:Exome Sequencing
Autosomal recessive non-syndromic hearing loss; COL1A1 C-propeptide cleavage site; Mosaicism; Next generation sequencing; Osteogenesis imperfecta; PDZD7