Copy-number analysis from genome sequencing data of 11,754 rare-disease parent-child trios: A model for identifying autosomal recessive human gene knockouts including a novel gene for autosomal recessive retinopathy.

Purpose: In parent-child trios with genome sequencing data, we investigated inherited biallelic deletions to identify known and novel genetic disorders.

Methods: We developed a copy-number variations analysis pipeline based on autosomal genome sequencing read depth of Genomics England 100,000 Genomes Project data from 11,754 parent-child trios and additional 18,875 non-trios. A control cohort of 15,440 cancer patients provided independent deletion frequencies.

Use of whole genome sequencing to determine the genetic basis of visceral myopathies including Prune Belly syndrome.

Objectives/aims: The visceral myopathies (VM) are a group of disorders characterised by poorly contractile or acontractile smooth muscle. They manifest in both the GI and GU tracts, ranging from megacystis to Prune Belly syndrome. We aimed to apply a bespoke virtual genetic panel and describe novel variants associated with this condition using whole genome sequencing data within the Genomics England 100,000 Genomes Project.

Molecular genetic diagnosis of kidney ciliopathies: Lessons from interpreting genomic sequencing data and the requirement for accurate phenotypic data.

Introduction: Massively parallel sequencing (MPS) techniques have made a major impact on the identification of the genetic basis of inherited kidney diseases such as the ciliopathy autosomal dominant polycystic kidney disease (ADPKD). Great care must be taken when analysing MPS data in isolation from accurate phenotypic information, as this can cause misdiagnosis.

Methods: Here, we describe a family trio, recruited to the Genomics England 100,000 Genomes Project, labelled as having cystic kidney disease, who were genetically unsolved following routine data analysis pipelines.

Biallelic variants in CEP164 cause a motile ciliopathy-like syndrome.

Ciliopathies may be classed as primary or motile depending on the underlying ciliary defect and are usually considered distinct clinical entities. Primary ciliopathies are associated with multisystem syndromes typically affecting the brain, kidney, and eye, as well as other organ systems such as the liver, skeleton, auditory system, and metabolism. Motile ciliopathies are a heterogenous group of disorders with defects in specialised motile ciliated tissues found within the lung, brain, and reproductive system, and are associated with primary ciliary dyskinesia, bronchiectasis, infertility and rarely hydrocephalus.

Monoallelic pathogenic ALG5 variants cause atypical polycystic kidney disease and interstitial fibrosis.

Disorders of the autosomal dominant polycystic kidney disease (ADPKD) spectrum are characterized by the development of kidney cysts and progressive kidney function decline. PKD1 and PKD2, encoding polycystin (PC)1 and 2, are the two major genes associated with ADPKD; other genes include IFT140, GANAB, DNAJB11, and ALG9. Genetic testing remains inconclusive in ∼7% of the families.