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Loss-of-function variants in DNM1 cause a specific form of developmental and epileptic encephalopathy only in biallelic ...

Published in Journal of medical genetics

Developmental and epileptic encephalopathies (DEEs) represent a group of severe neurological disorders characterised by an onset of refractory seizures during infancy or early childhood accompanied by psychomotor developmental delay or regression. DEEs are genetically heterogeneous with, to date, more than 80 different genetic subtypes including DE...

Phenotypic spectrum and genomics of undiagnosed arthrogryposis multiplex congenita.

Published in Journal of medical genetics

Arthrogryposis multiplex congenita (AMC) is characterised by congenital joint contractures in two or more body areas. AMC exhibits wide phenotypic and genetic heterogeneity. Our goals were to improve the genetic diagnosis rates of AMC, to evaluate the added value of whole exome sequencing (WES) compared with targeted exome sequencing (TES) and to i...

Characterisation of protein-truncating and missense variants in PALB2 in 15 768 women from Malaysia and Singapore.

Published in Journal of medical genetics

Rare protein-truncating variants (PTVs) in partner and localiser of BRCA2 (PALB2) confer increased risk to breast cancer, but relatively few studies have reported the prevalence in South-East Asian populations. Here, we describe the prevalence of rare variants in PALB2 in a population-based study of 7840 breast cancer cases and 7928 healthy Chinese...

Homozygous mutation in MCM7 causes autosomal recessive primary microcephaly and intellectual disability.

Published in Journal of medical genetics

Minichromosomal maintenance (MCM) complex components 2, 4, 5 and 6 have been linked to human disease with phenotypes including microcephaly and intellectual disability. The MCM complex has DNA helicase activity and is thereby important for the initiation and elongation of the replication fork and highly expressed in proliferating neural stem cells....

Mutations in phospholipase C eta-1 (PLCH1) are associated with holoprosencephaly.

Published in Journal of medical genetics

Holoprosencephaly is a spectrum of developmental disorder of the embryonic forebrain in which there is failed or incomplete separation of the prosencephalon into two cerebral hemispheres. To date, dominant mutations in sonic hedgehog (SHH) pathway genes are the predominant Mendelian causes, and have marked interfamilial and intrafamilial phenotypic...

Personalised virtual gene panels reduce interpretation workload and maintain diagnostic rates of proband-only clinical e...

Published in Journal of medical genetics

The increased adoption of genomic strategies in the clinic makes it imperative for diagnostic laboratories to improve the efficiency of variant interpretation. Clinical exome sequencing (CES) is becoming a valuable diagnostic tool, capable of meeting the diagnostic demand imposed by the vast array of different rare monogenic disorders. We have asse...

Using data from the 100,000 Genomes Project to resolve conflicting interpretations of a recurrent TUBB2A mutation.

Published in Journal of medical genetics

Improving the clinical interpretation of missense variants in X linked genes using structural analysis.

Published in Journal of medical genetics

Improving the clinical interpretation of missense variants can increase the diagnostic yield of genomic testing and lead to personalised management strategies. Currently, due to the imprecision of bioinformatic tools that aim to predict variant pathogenicity, their role in clinical guidelines remains limited. There is a clear need for more accurate...

Advances in genetic technologies result in improved diagnosis of mismatch repair deficiency in colorectal and endometria...

Published in Journal of medical genetics

Testing cancers for mismatch repair deficiency (dMMR) by immunohistochemistry (IHC) is a quick and inexpensive means of triaging individuals for germline Lynch syndrome testing. The aim of this study was to evaluate tumour dMMR and the prevalence of Lynch syndrome in patients referred to the Manchester Centre for Genomic Medicine, which serves a po...

Whole genome and exome sequencing identify NDUFV2 mutations as a new cause of progressive cavitating leukoencephalopathy...

Published in Journal of medical genetics

Progressive cavitating leukoencephalopathy (PCL) is thought to result from mutations in nuclear genes affecting mitochondrial function and energy metabolism. To date, mutations in two subunits of complex I, NDUFS1 and NDUFV1, have been reported to be related to PCL. Patients underwent clinical examinations, brain MRI, skin biopsy and muscle biopsy....