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The use of genome-wide sequencing (GWS) in paediatrics has added complexity to informed consent (IC) and pretest counselling because of the vast number and interpretation of potential findings, and their implications. However, empirical data from continental Europe on these issues remains limited. This study therefore aimed to explore the experiences and views of medical geneticists working with children in Germany and Switzerland regarding the challenges of obtaining valid IC in paediatric GWS. Qualitative interviews with 20 medical geneticists were analysed employing reflexive thematic analysis. In the interviews, many medical geneticists questioned the validity of parents’ IC due to the enormous amount of relevant information given and the variety and complexity of the possible test outcomes. Key barriers identified included familial implications, administrative challenges and struggles with non-directiveness. Medical geneticists’ suggestions for improvement included increasing the number of genetics professionals and better information material, which is crucial as GWS becomes a diagnostic standard in the early care pathways of children. An adjustment of aspirations from still existing ideal of traditional fully IC to appropriate IC seems to be needed. Such a more realistic and ethically sound adaptation of the requirements for IC can lead to better ‘informedness’ and improve the validity of the consent. This might also help reduce the moral distress for the medical geneticists involved.

Technological advances in both genome sequencing and prenatal imaging are increasing our ability to accurately recognize and diagnose Mendelian conditions prenatally. Phenotype‐driven early genetic diagnosis of fetal genetic disease can help to strategize treatment options and clinical preventive measures during the perinatal period, to plan in utero therapies, and to inform parental decision‐making. Fetal phenotypes of genetic diseases are often unique and at present are not well understood; more comprehensive knowledge about prenatal phenotypes and computational resources have an enormous potential to improve diagnostics and translational research. The Human Phenotype Ontology (HPO) has been widely used to support diagnostics and translational research in human genetics. To better support prenatal usage, the HPO consortium conducted a series of workshops with a group of domain experts in a variety of medical specialties, diagnostic techniques, as well as diseases and phenotypes related to prenatal medicine, including perinatal pathology, musculoskeletal anomalies, neurology, medical genetics, hydrops fetalis, craniofacial malformations, cardiology, neonatal‐perinatal medicine, fetal medicine, placental pathology, prenatal imaging, and bioinformatics. We expanded the representation of prenatal phenotypes in HPO by adding 95 new phenotype terms under the Abnormality of prenatal development or birth(HP:0001197) grouping term, and revised definitions, synonyms, and disease annotations for most of the 152 terms that existed before the beginning of this effort. The expansion of prenatal phenotypes in HPO will support phenotype‐driven prenatal exome and genome sequencing for precision genetic diagnostics of rare diseases to support prenatal care.

Uni- or bilateral renal agenesis (RA) is a commonly occurring major congenital anomaly impacting fetal and neonatal outcomes. Since the etiology is highly heterogeneous, our aim was to provide a logically structured approach by highlighting the genes in which variants have been identified to be associated with RA and to define the pathways involved in this type of abnormal kidney development. We used Phenolyzer to collect a list of all the genes known as causative for RA. Using ClueGO gene enrichment analysis, we classified the relationship between these genes and the biological processes defined by gene ontology. We identified 287 genes and 69 groups of enriched biological processes. About 50% included pathways directly related to the development of urogenital organ tissues. Several ciliary, axis specification, hindgut development, and endocrine pathways were enriched, which may relate to different clinical presentations of RA. Our gene ontology enrichment analysis shows that genes representing distinct biological pathways are significantly enriched. This knowledge will lead to an improved molecular diagnosis in clinical care when applying genome-wide sequencing approaches. The findings will also allow to further study the biological pathways involved in RA and to identify novel candidate genes and pathways.

Motor kinesins are a family of evolutionary conserved proteins involved in intracellular trafficking of various cargoes, first described in the context of axonal transport. They were discovered to have a key importance in cell-cycle dynamics and progression, including chromosomal condensation and alignment, spindle formation and cytokinesis, as well as ciliogenesis and cilia function. Recent evidence suggests that impairment of kinesins is associated with a variety of human diseases consistent with their functions and evolutionary conservation. Through the advent of gene identification using genome-wide sequencing approaches, their role in monogenic disorders now emerges, particularly for birth defects, in isolated as well as multiple congenital anomalies. We can observe recurrent phenotypical themes such as microcephaly, certain brain anomalies, and anomalies of the kidney and urinary tract, as well as syndromic phenotypes reminiscent of ciliopathies. Together with the molecular and functional data, we suggest understanding these ‘kinesinopathies’ as a recognisable entity with potential value for research approaches and clinical care.

Stromme syndrome.

The monogenic etiology of most severe fetal anomaly syndromes is poorly understood. Our objective was to use exome sequencing (ES) to increase our knowledge on causal variants and novel candidate genes associated with specific fetal phenotypes. We employed ES in a cohort of 19 families with one or more fetuses presenting with a distinctive anomaly pattern and/or phenotype recurrence at increased risk for lethal outcomes. Candidate variants were identified in 12 families (63%); in 6 of them a definite diagnosis was achieved including known or novel variants in recognized disease genes (MKS1, OTX2, FGFR2, and RYR1)and variants in novel disease genes describing new fetal phenotypes (CENPF, KIF14). We identified variants likely causal after clinical and functional review (SMAD3, KIF4A, and PIGW) and propose novel candidate genes (PTK7, DNHD1, and TTC28) for early human developmental disease supported by functional and cross-species phenotyping evidence. We describe rare and novel fetal anomaly syndromes and highlight the diagnostic utility of ES, but also its contribution to discovery. The diagnostic yield of the future application of prenatal ES will depend on our ability to increase our knowledge on the specific phenotype–genotype correlations during fetal development.

Interstitial deletions of 1q4 are rare and present with different deletion breakpoints and variable phenotype. We report on the clinical and molecular cytogenetic findings in a girl with minor anomalies, midline defects including prenatally ascertained agenesis of the corpus callosum, epilepsy and developmental delay. A de novo 5.45 Mb deletion almost exclusively located within 1q42 was found to cause this phenotype, which shows significant overlap with the microdeletion 1q41q42 syndrome reported in a few patients except for the agenesis of the corpus callosum. However, deletions in patients with the 1q41q42 syndrome mainly extend into the 1q41 region with a region of overlap including the DISP1gene involved in the SHH pathway, which is not part of the 1q42 deletion in our patient. We suggest that an interaction of genes involved in pathways of embryonic development rather than haploinsufficiency of single genes in the socalled critical regions is causing complex malformation syndromes due to cytogenetic microaberrations in the 1q4 region. © 2010 WileyLiss, Inc.

We report on the clinical and cytogenetic findings as well as the arraybased characterization of an interstitial familial 13q21 deletion initially recognized by standard karyotyping. Although 13q deletions are known to imply a wide variability of clinical consequences, the deletion carriers of the familial deletion in three generations did not reveal a relevant phenotype. The breakpoints and the deletion size in all three carrier individuals were determined by molecular karyotyping confirming a large 14.5 Mb deletion encompassing the 13q21.1–13q21.33 region identical in all three carriers. Gene paucity and the lack of dosagesensitive genes in the delineated region might explain the apparently innocuous nature of this chromosomal anomaly. The example of this family presents evidence for describing the chromosomal region 13q21.1–13q21.33 as a large euchromatic variant or benign copy number variation without phenotypic consequences. Our data underline the importance of a phenogenetic approach combining clinical and laboratory evidence in the interpretation of segmental chromosomal anomalies especially in genetic counseling related to prenatal diagnosis. © 2009 WileyLiss, Inc.

No Abstract.

We report on two patients with de novo subtelomeric terminal deletion of chromosome 6p. Patient 1 is an 8monthold female born with normal growth parameters, typical facial features of 6pter deletion, bilateral corectopia, and protruding tongue. She has severe developmental delay, profound bilateral neurosensory deafness, poor visual contact, and hypsarrhythmia since the age of 6 months. Patient 2 is a 5yearold male born with normal growth parameters and unilateral hip dysplasia; he has a characteristic facial phenotype, bilateral embryotoxon, and moderate mental retardation. Further characterization of the deletion, using highresolution array comparative genomic hybridization arrayCGH; Agilent Human Genome kit 244 K, revealed that Patient 1 has a 8.1 Mb 6pter6p24.3 deletion associated with a contiguous 5.8 Mb 6p24.36p24.1 duplication and Patient 2 a 5.7 Mb 6pter6p25.1 deletion partially overlapping with that of Patient 1. Complementary FISH and array analysis showed that the inv del dup6 in Patient 1 originated de novo. Our results demonstrate that simple rearrangements are often more complex than defined by standard techniques. We also discuss genotype–phenotype correlations including previously reported cases of deletion 6p. © 2008 WileyLiss, Inc.