Multi-locus imprinting disturbance (MLID): interim joint statement for clinical and molecular diagnosis.

Background: Imprinting disorders are rare diseases resulting from altered expression of imprinted genes, which exhibit parent-of-origin-specific expression patterns regulated through differential DNA methylation. A subgroup of patients with imprinting disorders have DNA methylation changes at multiple imprinted loci, a condition referred to as multi-locus imprinting disturbance (MLID). MLID is recognised in most but not all imprinting disorders and is also found in individuals with atypical clinical features; the presence of MLID often alters the management or prognosis of the affected person.

Long-term Follow-up of a Late Diagnosed Patient with Temple Syndrome.

Temple syndrome is a rare imprinting disorder, caused by alterations in the critical imprinted region 14q32 of chromosome 14. It is characterized by pre- and postnatal growth retardation, truncal hypotonia and facial dysmorphism in the neonatal period. We report an 18-year-old girl with a late diagnosis of Temple syndrome presenting with all typical signs and symptoms including small for gestational age at birth, feeding difficulties, muscle hypotonia and delayed developmental milestones, central precocious puberty, truncal obesity and reduced growth.

First step towards a consensus strategy for multi-locus diagnostic testing of imprinting disorders.

Background: Imprinting disorders, which affect growth, development, metabolism and neoplasia risk, are caused by genetic or epigenetic changes to genes that are expressed from only one parental allele. Disease may result from changes in coding sequences, copy number changes, uniparental disomy or imprinting defects. Some imprinting disorders are clinically heterogeneous, some are associated with more than one imprinted locus, and some patients have alterations affecting multiple loci.

Ongoing Challenges in the Diagnosis of 11p15.5-Associated Imprinting Disorders.

The overgrowth disorder Beckwith-Wiedemann syndrome and the growth restriction disorder Silver-Russell syndrome have been described as 'mirror' syndromes, in both their clinical features and molecular causes. Clinically, their nonspecific features, focused around continuous variables of atypical growth, make it hard to set diagnostic thresholds that are pragmatic without potentially excluding some cases. Molecularly, both are imprinting disorders, classically associated with 'opposite' genetic and epigenetic changes to genes on chromosome 11p15, but both are associated with somatic mosaicism as well as an increasing range of alternative (epi)genetic changes to other genes, which make molecular diagnosis an increasingly complex process.

Trans-acting genetic variants causing multilocus imprinting disturbance (MLID): common mechanisms and consequences.

Background: Imprinting disorders are a group of congenital diseases which are characterized by molecular alterations affecting differentially methylated regions (DMRs). To date, at least twelve imprinting disorders have been defined with overlapping but variable clinical features including growth and metabolic disturbances, cognitive dysfunction, abdominal wall defects and asymmetry. In general, a single specific DMR is affected in an individual with a given imprinting disorder, but there are a growing number of reports on individuals with so-called multilocus imprinting disturbances (MLID), where aberrant imprinting marks (most commonly loss of methylation) occur at multiple DMRs.

A patient with multilocus imprinting disturbance involving hypomethylation at 11p15 and 14q32, and phenotypic features of Beckwith-Wiedemann and Temple syndromes.

Beckwith-Wiedemann syndrome (BWS) and Temple syndrome (TS) are classical imprinting disorders (IDs) with nonconfluent clinical features. We report here on a patient with clinical features of both syndromes, in whom epimutations were found at the BWS and TS imprinted regions, consistent with multilocus imprinting disturbance (MLID). This is the first case report of a patient with clinical features of both conditions who was found to have loss of methylation (LOM) of KCNQ1OT1: TSS-DMR (ICR2) in the 11p15 imprinted region associated with BWS and LOM of MEG3: TSS-DMR in the 14q32 imprinted region associated with TS.

Height and body mass index in molecularly confirmed Silver-Russell syndrome and the long-term effects of growth hormone treatment.

Objective: Silver-Russell syndrome (SRS) causes short stature. Growth hormone (GH) treatment aims to increase adult height. However, data are limited on the long-term outcomes of GH in patients with molecularly confirmed SRS.

100,000 Genomes Pilot on Rare-Disease Diagnosis in Health Care - Preliminary Report.

Background: The U.K. 100,000 Genomes Project is in the process of investigating the role of genome sequencing in patients with undiagnosed rare diseases after usual care and the alignment of this research with health care implementation in the U.

Whole-genome analysis as a diagnostic tool for patients referred for diagnosis of Silver-Russell syndrome: a real-world study.

Background: Silver-Russell syndrome (SRS) is an imprinting disorder characterised by prenatal and postnatal growth restriction, but its clinical features are non-specific and its differential diagnosis is broad. Known molecular causes of SRS include imprinting disturbance, single nucleotide variant (SNV), CNV or UPD affecting several genes; however, up to 40% of individuals with a clinical diagnosis of SRS currently receive no positive molecular diagnosis.

Methods: To determine whether whole-genome sequencing (WGS) could uncover pathogenic variants missed by current molecular testing, we analysed data of 72 participants recruited to the 100,000 Genomes Project within the clinical category of SRS.

Activating mutations in BRAF disrupt the hypothalamo-pituitary axis leading to hypopituitarism in mice and humans.

Germline mutations in BRAF and other components of the MAPK pathway are associated with the congenital syndromes collectively known as RASopathies. Here, we report the association of Septo-Optic Dysplasia (SOD) including hypopituitarism and Cardio-Facio-Cutaneous (CFC) syndrome in patients harbouring mutations in BRAF. Phosphoproteomic analyses demonstrate that these genetic variants are gain-of-function mutations leading to activation of the MAPK pathway.

Experiences of adolescents living with Silver-Russell syndrome.

Objective: The psychosocial impact of growing up with Silver-Russell syndrome (SRS), characterised by growth failure and short stature in adulthood, has been explored in adults; however, there are no accounts of contemporary lived experience in adolescents. Such data could inform current healthcare guidance and transition to adult services. We aimed to explore the lived experience of adolescents with SRS.

Successful pregnancies in an adult with Meier-Gorlin syndrome harboring biallelic CDT1 variants.

Meier-Gorlin syndrome is an autosomal recessively inherited disorder of growth retardation, accompanied by microtia and patellae a/hypoplasia and characteristic facies. Pathogenic variants in genes associated with the initiation of DNA replication underlie the condition, with biallelic variants in CDT1 the most common cause. Using 10× Chromium genome sequencing, we report CDT1 variants in an adult female, with an inframe amino acid deletion inherited in trans with a deep intronic variant which likely serves as the branchpoint site in Intron 8.

DNA Methylation Signature for EZH2 Functionally Classifies Sequence Variants in Three PRC2 Complex Genes.

Weaver syndrome (WS), an overgrowth/intellectual disability syndrome (OGID), is caused by pathogenic variants in the histone methyltransferase EZH2, which encodes a core component of the Polycomb repressive complex-2 (PRC2). Using genome-wide DNA methylation (DNAm) data for 187 individuals with OGID and 969 control subjects, we show that pathogenic variants in EZH2 generate a highly specific and sensitive DNAm signature reflecting the phenotype of WS. This signature can be used to distinguish loss-of-function from gain-of-function missense variants and to detect somatic mosaicism.

Phenotype of genetically confirmed Silver-Russell syndrome beyond childhood.

Background: Silver-Russell syndrome is an imprinting disorder that restricts growth, resulting in short adult stature that may be ameliorated by treatment. Approximately 50% of patients have loss of methylation of the imprinting control region (H19/IGF2:IG-DMR) on 11p15.5 and 5%-10% have maternal uniparental disomy of chromosome 7.

HIST1H1E heterozygous protein-truncating variants cause a recognizable syndrome with intellectual disability and distinctive facial gestalt: A study to clarify the HIST1H1E syndrome phenotype in 30 individuals.

Histone Gene Cluster 1 Member E, HIST1H1E, encodes Histone H1.4, is one of a family of epigenetic regulator genes, acts as a linker histone protein, and is responsible for higher order chromatin structure. HIST1H1E syndrome (also known as Rahman syndrome, OMIM #617537) is a recently described intellectual disability (ID) syndrome.

Growth disrupting mutations in epigenetic regulatory molecules are associated with abnormalities of epigenetic aging.

Germline mutations in fundamental epigenetic regulatory molecules including DNA methyltransferase 3 alpha () are commonly associated with growth disorders, whereas somatic mutations are often associated with malignancy. We profiled genome-wide DNA methylation patterns in c.2312G > A; p.

Growth Hormone Improves Short-Term Growth in Patients with Temple Syndrome.

Background/aims: Temple syndrome is an imprinting disorder caused by maternal uniparental disomy of chromosome 14 (mat UPD14), paternal deletion of 14q32 or paternal hypomethylation of the intergenic differentially methylated region (MEG3/DLK1 IG-DMR). Patients with Temple syndrome have pre- and postnatal growth restriction, short stature, hypotonia, small hands and feet and precocious puberty. We sought to determine whether treatment with growth hormone improves growth outcomes in patients with Temple syndrome.

Discrepant molecular and clinical diagnoses in Beckwith-Wiedemann and Silver-Russell syndromes.

Beckwith-Wiedemann syndrome (BWS) and Silver-Russell syndrome (SRS) are two imprinting disorders associated with opposite molecular alterations in the 11p15.5 imprinting centres. Their clinical diagnosis is confirmed by molecular testing in 50-70% of patients.

Correction: Germline mutations in the oncogene EZH2 cause Weaver syndrome and increased human height.

[This corrects the article DOI: 10.18632/oncotarget.385.

Pathogenicity and selective constraint on variation near splice sites.

Mutations that perturb normal pre-mRNA splicing are significant contributors to human disease. We used exome sequencing data from 7833 probands with developmental disorders (DDs) and their unaffected parents, as well as more than 60,000 aggregated exomes from the Exome Aggregation Consortium, to investigate selection around the splice sites and quantify the contribution of splicing mutations to DDs. Patterns of purifying selection, a deficit of variants in highly constrained genes in healthy subjects, and excess de novo mutations in patients highlighted particular positions within and around the consensus splice site of greater functional relevance.

Genetics, molar pregnancies and medieval ideas of monstrous births: the lump of flesh in .

The medieval English romance gives an account of a birth of a lump of flesh. This has been considered as fantastic and monstrous in past literature, the horrific union of a Christian and Saracen. However, while the text certainly speaks to miscegenation, we propose that this lump of flesh is actually a hydatidiform mole.