Couples at risk of transmitting a genetic disease to their offspring may experience doubts about their reproductive options. This study examines the effects of an online decision aid (DA) on the ... Show moreCouples at risk of transmitting a genetic disease to their offspring may experience doubts about their reproductive options. This study examines the effects of an online decision aid (DA) on the (joint) reproductive decision-making process of couples (not pregnant at time of inclusion) at risk of transmitting a genetic disease to their offspring. The primary outcome is decisional conflict, and secondary outcomes are knowledge, realistic expectations, deliberation, joint informed decision-making, and decisional self-efficacy. These outcomes were measured with a pretest-posttest design: before use (T0), after use (T1), and 2 weeks after use (T2) of the decision aid (DA). Usability of the DA was assessed at T1. Paired sample t-tests were used to compute differences between baseline and subsequent measurements. The comparisons of T0-T1 and T0-T2 indicate a significant reduction in mean decisional conflict scores with stronger effects for participants with high baseline decisional conflict scores. Furthermore, use of the DA led to increased knowledge, improved realistic expectations, and increased levels of deliberation, with higher increase in participants with low baseline scores. Decision self-efficacy only improved for participants with lower baseline scores. Participants indicated that the information in the DA was comprehensible and clearly organized. These first results indicate that this online DA is an appropriate tool to support couples at risk of transmitting a genetic disease and a desire to have (a) child(ren) in their reproductive decision-making process. Show less
Sluijs, P.J. van der; Alders, M.; Dingemans, A.J.M.; Parbhoo, K.; Bon, B.W. van; Dempsey, J.C.; ... ; Santen, G.W.E. 2021
ANKRD17 is an ankyrin repeat-containing protein thought to play a role in cell cycle progression, whose ortholog in Drosophila functions in the Hippo pathway as a co-factor of Yorkie. Here, we... Show moreANKRD17 is an ankyrin repeat-containing protein thought to play a role in cell cycle progression, whose ortholog in Drosophila functions in the Hippo pathway as a co-factor of Yorkie. Here, we delineate a neurodevelopmental disorder caused by de novo heterozygous ANKRD17 variants. The mutational spectrum of this cohort of 34 individuals from 32 families is highly suggestive of haploinsufficiency as the underlying mechanism of disease, with 21 truncating or essential splice site variants, 9 missense variants, 1 in-frame insertion-deletion, and 1 microdeletion (1.16 Mb). Consequently, our data indicate that loss of ANKRD17 is likely the main cause of phenotypes previously associated with large multi-gene chromosomal aberrations of the 4q13.3 region. Protein modeling suggests that most of the missense variants disrupt the stability of the ankyrin repeats through alteration of core structural residues. The major phenotypic characteristic of our cohort is a variable degree of developmental delay/intellectual disability, particularly affecting speech, while additional features include growth failure, feeding difficulties, non-specific MRI abnormalities, epilepsy and/or abnormal EEG, predisposition to recurrent infections (mostly bacterial), ophthalmological abnormalities, gait/balance disturbance, and joint hypermobility. Moreover, many individuals shared similar dysmorphic facial features. Analysis of single-cell RNA-seq data from the developing human telencephalon indicated ANKRD17 expression at multiple stages of neurogenesis, adding further evidence to the assertion that damaging ANKRD17 variants cause a neurodevelopmental disorder. Show less
Boschann, F.; Stuurman, K.E.; Bruin, C. de; Slegtenhorst, M. van; Duyvenvoorde, H.A. van; Kant, S.G.; Ehmke, N. 2019
Catel-Manzke syndrome, also known as micrognathia-digital-syndrome, is a rare autosomal recessive disorder characterized by the combination of the two cardinal features Pierre-Robin sequence and... Show moreCatel-Manzke syndrome, also known as micrognathia-digital-syndrome, is a rare autosomal recessive disorder characterized by the combination of the two cardinal features Pierre-Robin sequence and bilateral hyperphalangy leading to ulnar clinodactyly (ulnar curvature of the phalanges) and radial deviation (radial angulation at the metacarpophalangeal joint) of the index fingers. Individuals without one of these major hallmarks or with additional hand malformations have been described as atypical or Catel-Manzke-like syndrome. Biallelic TGDS pathogenic variants have thus far been detected in eight individuals with typical Catel-Manzke syndrome and in one fetus with additional features. Here we report on two individuals with TGDS pathogenic variants who presented with mild radial deviation and ulnar clinodactyly of the index fingers but without radiologic signs of hyperphalangy. Furthermore, both individuals have disproportionate short stature, a feature that has not yet been associated with Catel-Manzke syndrome. Our data broaden the phenotypic spectrum of TGDS-associated Catel-Manzke syndrome and expand the indication for diagnostic testing. Show less
