Mutations in the Histone Modifier PRDM6 Are Associated with Isolated Nonsyndromic Patent Ductus Arteriosus.

Nonsyndromic patent ductus arteriosus (PDA) is a common congenital heart defect (CHD) with both inherited and acquired causes, but the disease mechanisms have remained elusive. Using combined genome-wide linkage analysis and whole-exome sequencing (WES), we identified independent mutations in PRDM6, which encodes a nuclear protein that is specific to vascular smooth muscle cells (VSMC), has histone methyl transferase activities, and acts as a transcriptional suppressor of contractile proteins. In vitro assays showed that the mutations cause loss of function either by intracellular redistribution of the protein and/or by alteration of its methyltransferase activities. Wild-type embryonic ductus arteriosus (DA) exhibited high levels of PRDM6, which rapidly declined postnatally as the number of VSMCs necessary for ductus contraction increased. This dynamic change suggests that PRDM6 plays a key role in maintaining VSMCs in an undifferentiated stage in order to promote their proliferation and that its loss of activity results in premature differentiation and impaired remodeling of the DA. Our findings identify PRDM6 mutations as underlying genetic causes of nonsyndromic isolated PDA in humans and implicates the wild-type protein in epigenetic regulation of ductus remodeling.

The genetic basis of DOORS syndrome: an exome-sequencing study.

BACKGROUND: Deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures (DOORS) syndrome is a rare autosomal recessive disorder of unknown cause. We aimed to identify the genetic basis of this syndrome by sequencing most coding exons in affected individuals. METHODS: Through a search of available case studies and communication with collaborators, we identified families that included at least one individual with at least three of the five main features of the DOORS syndrome: deafness, onychodystrophy, osteodystrophy, intellectual disability, and seizures. Participants were recruited from 26 centres in 17 countries. Families described in this study were enrolled between Dec 1, 2010, and March 1, 2013. Collaborating physicians enrolling participants obtained clinical information and DNA samples from the affected child and both parents if possible. We did whole-exome sequencing in affected individuals as they were enrolled, until we identified a candidate gene, and Sanger sequencing to confirm mutations. We did expression studies in human fibroblasts from one individual by real-time PCR and western blot analysis, and in mouse tissues by immunohistochemistry and real-time PCR. FINDINGS: 26 families were included in the study. We did exome sequencing in the first 17 enrolled families; we screened for TBC1D24 by Sanger sequencing in subsequent families. We identified TBC1D24 mutations in 11 individuals from nine families (by exome sequencing in seven families, and Sanger sequencing in two families). 18 families had individuals with all five main features of DOORS syndrome, and TBC1D24 mutations were identified in half of these families. The seizure types in individuals with TBC1D24 mutations included generalised tonic-clonic, complex partial, focal clonic, and infantile spasms. Of the 18 individuals with DOORS syndrome from 17 families without TBC1D24 mutations, eight did not have seizures and three did not have deafness. In expression studies, some mutations abrogated TBC1D24 mRNA stability. We also detected Tbc1d24 expression in mouse phalangeal chondrocytes and calvaria, which suggests a role of TBC1D24 in skeletogenesis. INTERPRETATION: Our findings suggest that mutations in TBC1D24 seem to be an important cause of DOORS syndrome and can cause diverse phenotypes. Thus, individuals with DOORS syndrome without deafness and seizures but with the other features should still be screened for TBC1D24 mutations. More information is needed to understand the cellular roles of TBC1D24 and identify the genes responsible for DOORS phenotypes in individuals who do not have a mutation in TBC1D24. FUNDING: US National Institutes of Health, the CIHR (Canada), the NIHR (UK), the Wellcome Trust, the Henry Smith Charity, and Action Medical Research.

Expanding the phenotype of oculoectodermal syndrome: possible relationship to encephalocraniocutaneous lipomatosis.

Oculoectodermal syndrome (OES) is characterized by epibulbar dermoids, aplasia cutis congenita, and other abnormalities. Here, we report 2 new cases, review 13 previous cases, and propose that OES may be a mild variant of encephalocraniocutaneous lipomatosis (ECCL), differing primarily in its lack of intracranial pathology.

Attitudes of families affected by adrenoleukodystrophy toward prenatal diagnosis, presymptomatic and carrier testing, and newborn screening.

Families affected by adrenoleukodystrophy (ALD) and adrenomyeloneuropathy (AMN) were surveyed to elicit attitudes toward prenatal, presymptomatic and carrier testing, and newborn screening in order to determine the level of support that these families have for current and future genetic testing protocols. Identifying attitudes toward genetic testing, including newborn screening, is especially important because of new data regarding therapeutic options and the possible addition of ALD to newborn screening regimens. The Kennedy Krieger Institute (KKI) database identified 327 prospective participants. Families that were willing to participate in the study received an anonymous questionnaire for completion. Frequencies were generated using SPSS software for Windows. Questionnaires were returned from 128 families for a response rate of 39%. Sons who were at risk for inheriting the ALD gene would be tested by 93% of respondents, and 89.3% would ideally have this testing performed prenatally or in the newborn period. Eighty-nine percent would test an at-risk daughter and 51.2% would ideally have this testing performed prenatally or shortly after birth. ALD newborn screening for males and females was supported by 90% of respondents. If newborn screening for ALD/AMN commences, or there is a new diagnosis of ALD, genetic professionals need to be prepared to have extensive conversations with families regarding the benefits and limitations of current therapeutic and genetic testing options.

Training for genetic counsellors.

Genetic counsellors are uniquely trained to provide support, explanations and guidance to individuals or families who have been diagnosed with a genetic disorder. As our knowledge of the genetic basis of disease increases, so does our ability to diagnose it and so does the demand for appropriately trained genetic counsellors. Despite this growing demand, only a handful of countries provides formal courses in genetic counselling, whereas other countries leave genetic counselling in the hands of medical practitioners or medical geneticists.

Drowning as a cause of death in Angelman syndrome.

Angelman syndrome is characterized by mental retardation, seizures, ataxia, inappropriate laughter, lack of speech, a particular facial appearance, and generally a chromosome 15q11-q13 deletion. Recently, a fascination with water and water-related activities has been reported in individuals with the syndrome. We report on a 9.6-year-old male previously diagnosed with Angelman syndrome who died unexpectedly by drowning in a shallow backyard wading pool. This case further illustrates the fascination with water by individuals with Angelman syndrome and highlights that this fascination may lead to death. We wish to alert careproviders that this fascination with water and water-related activities may contribute to death and that these individuals should be closely supervised when in the presence of water.

Oculoauriculofrontonasal syndrome (OAFNS) in a nine-month-old male.

We report a nine-month-old Caucasian male with features seen in oculoauriculovertebral spectrum (OAVS) and frontonasal dysplasia sequence (FND) born to normal, non-consanguineous parents and review the literature. His malformations included a left pre-auricular skin tag, severely hypoplastic right pinna without an external canal, severely everted and hypoplastic left upper eyelid, bilateral cleft lip and palate, bifid broad nasal tip, ocular hypertelorism, micrognathia, hypoplastic mandible, an extra cervical rib on the left, hemivertebrae at T3-4, agenesis of the posterior corpus callosum with a midline lipoma, and an extra renal pelvis. This constellation of anomalies is consistent with the diagnosis of oculoauriculofrontonasal syndrome (OAFNS) which appears to be a distinct condition from either OAVS or FND but with overlapping features.