A Mild PUM1 Mutation Is Associated with Adult-Onset Ataxia, whereas Haploinsufficiency Causes Developmental Delay and Seizures.

Certain mutations can cause proteins to accumulate in neurons, leading to neurodegeneration. We recently showed, however, that upregulation of a wild-type protein, Ataxin1, caused by haploinsufficiency of its repressor, the RNA-binding protein Pumilio1 (PUM1), also causes neurodegeneration in mice. We therefore searched for human patients with PUM1 mutations. We identified eleven individuals with either PUM1 deletions or de novo missense variants who suffer a developmental syndrome (Pumilio1-associated developmental disability, ataxia, and seizure; PADDAS). We also identified a milder missense mutation in a family with adult-onset ataxia with incomplete penetrance (Pumilio1-related cerebellar ataxia, PRCA). Studies in patient-derived cells revealed that the missense mutations reduced PUM1 protein levels by ∼25% in the adult-onset cases and by ∼50% in the infantile-onset cases; levels of known PUM1 targets increased accordingly. Changes in protein levels thus track with phenotypic severity, and identifying posttranscriptional modulators of protein expression should identify new candidate disease genes.

Short-read whole genome sequencing identifies causative variants in most individuals with previously unexplained aniridia.

BACKGROUND: Classic aniridia is a highly penetrant autosomal dominant disorder characterised by congenital absence of the iris, foveal hypoplasia, optic disc anomalies and progressive opacification of the cornea. >90% of cases of classic aniridia are caused by heterozygous, loss-of-function variants affecting the PAX6 locus. METHODS: Short-read whole genome sequencing was performed on 51 (39 affected) individuals from 37 different families who had screened negative for mutations in the PAX6 coding region. RESULTS: Likely causative mutations were identified in 22 out of 37 (59%) families. In 19 out of 22 families, the causative genomic changes have an interpretable deleterious impact on the PAX6 locus. Of these 19 families, 1 has a novel heterozygous PAX6 frameshift variant missed on previous screens, 4 have single nucleotide variants (SNVs) (one novel) affecting essential splice sites of PAX6 5' non-coding exons and 2 have deep intronic SNV (one novel) resulting in gain of a donor splice site. In 12 out of 19, the causative variants are large-scale structural variants; 5 have partial or whole gene deletions of PAX6, 3 have deletions encompassing critical PAX6 cis-regulatory elements, 2 have balanced inversions with disruptive breakpoints within the PAX6 locus and 2 have complex rearrangements disrupting PAX6. The remaining 3 of 22 families have deletions encompassing FOXC1 (a known cause of atypical aniridia). Seven of the causative variants occurred de novo and one cosegregated with familial aniridia. We were unable to establish inheritance status in the remaining probands. No plausibly causative SNVs were identified in PAX6 cis-regulatory elements. CONCLUSION: Whole genome sequencing proves to be an effective diagnostic test in most individuals with previously unexplained aniridia.

Clustered mutations in the GRIK2 kainate receptor subunit gene underlie diverse neurodevelopmental disorders.

Kainate receptors (KARs) are glutamate-gated cation channels with diverse roles in the central nervous system. Bi-allelic loss of function of the KAR-encoding gene GRIK2 causes a nonsyndromic neurodevelopmental disorder (NDD) with intellectual disability and developmental delay as core features. The extent to which mono-allelic variants in GRIK2 also underlie NDDs is less understood because only a single individual has been reported previously. Here, we describe an additional eleven individuals with heterozygous de novo variants in GRIK2 causative for neurodevelopmental deficits that include intellectual disability. Five children harbored recurrent de novo variants (three encoding p.Thr660Lys and two p.Thr660Arg), and four children and one adult were homozygous for a previously reported variant (c.1969G>A [p.Ala657Thr]). Individuals with shared variants had some overlapping behavioral and neurological dysfunction, suggesting that the GRIK2 variants are likely pathogenic. Analogous mutations introduced into recombinant GluK2 KAR subunits at sites within the M3 transmembrane domain (encoding p.Ala657Thr, p.Thr660Lys, and p.Thr660Arg) and the M3-S2 linker domain (encoding p.Ile668Thr) had complex effects on functional properties and membrane localization of homomeric and heteromeric KARs. Both p.Thr660Lys and p.Thr660Arg mutant KARs exhibited markedly slowed gating kinetics, similar to p.Ala657Thr-containing receptors. Moreover, we observed emerging genotype-phenotype correlations, including the presence of severe epilepsy in individuals with the p.Thr660Lys variant and hypomyelination in individuals with either the p.Thr660Lys or p.Thr660Arg variant. Collectively, these results demonstrate that human GRIK2 variants predicted to alter channel function are causative for early childhood development disorders and further emphasize the importance of clarifying the role of KARs in early nervous system development.

Narrowing the diagnostic gap: Genomes, episignatures, long-read sequencing, and health economic analyses in an exome-negative intellectual disability cohort.

PURPOSE: Genome sequencing (GS)-specific diagnostic rates in prospective tightly ascertained exome sequencing (ES)-negative intellectual disability (ID) cohorts have not been reported extensively. METHODS: ES, GS, epigenetic signatures, and long-read sequencing diagnoses were assessed in 74 trios with at least moderate ID. RESULTS: The ES diagnostic yield was 42 of 74 (57%). GS diagnoses were made in 9 of 32 (28%) ES-unresolved families. Repeated ES with a contemporary pipeline on the GS-diagnosed families identified 8 of 9 single-nucleotide variations/copy-number variations undetected in older ES, confirming a GS-unique diagnostic rate of 1 in 32 (3%). Episignatures contributed diagnostic information in 9% with GS corroboration in 1 of 32 (3%) and diagnostic clues in 2 of 32 (6%). A genetic etiology for ID was detected in 51 of 74 (69%) families. Twelve candidate disease genes were identified. Contemporary ES followed by GS cost US$4976 (95% CI: $3704; $6969) per diagnosis and first-line GS at a cost of $7062 (95% CI: $6210; $8475) per diagnosis. CONCLUSION: Performing GS only in ID trios would be cost equivalent to ES if GS were available at $2435, about a 60% reduction from current prices. This study demonstrates that first-line GS achieves higher diagnostic rate than contemporary ES but at a higher cost.

RLIM Is a Candidate Dosage-Sensitive Gene for Individuals with Varying Duplications of Xq13, Intellectual Disability, and Distinct Facial Features.

Interpretation of the significance of maternally inherited X chromosome variants in males with neurocognitive phenotypes continues to present a challenge to clinical geneticists and diagnostic laboratories. Here we report 14 males from 9 families with duplications at the Xq13.2-q13.3 locus with a common facial phenotype, intellectual disability (ID), distinctive behavioral features, and a seizure disorder in two cases. All tested carrier mothers had normal intelligence. The duplication arose de novo in three mothers where grandparental testing was possible. In one family the duplication segregated with ID across three generations. RLIM is the only gene common to our duplications. However, flanking genes duplicated in some but not all the affected individuals included the brain-expressed genes NEXMIF, SLC16A2, and the long non-coding RNA gene FTX. The contribution of the RLIM-flanking genes to the phenotypes of individuals with different size duplications has not been fully resolved. Missense variants in RLIM have recently been identified to cause X-linked ID in males, with heterozygous females typically having normal intelligence and highly skewed X chromosome inactivation. We detected consistent and significant increase of RLIM mRNA and protein levels in cells derived from seven affected males from five families with the duplication. Subsequent analysis of MDM2, one of the targets of the RLIM E3 ligase activity, showed consistent downregulation in cells from the affected males. All the carrier mothers displayed normal RLIM mRNA levels and had highly skewed X chromosome inactivation. We propose that duplications at Xq13.2-13.3 including RLIM cause a recognizable but mild neurocognitive phenotype in hemizygous males.

Health professionals' role in the transfer of mosaic embryos after preimplantation genetic testing for aneuploidies.

RESEARCH QUESTION: What are health professionals' clinical practices, views and self-rated competencies regarding the transfer of mosaic embryos? DESIGN: This was a cross-sectional study using surveys. RESULTS: Data were collected from the Royal Australian and New Zealand College of Obstetricians and Gynaecologists and the Fertility Society of Australia and New Zealand. Ninety-five responses were analysed and reported. The results show that most health professionals (n = 62) discussed the transfer of mosaic embryos for different reasons and raised concerns regarding various risks. Although many health professionals were unsure whether mosaic embryos should be transferred, they were more inclined to encourage transfer if the scenario involved segmental losses compared with mosaicism involving duplication of the entire chromosome (i.e. trisomy 21) (e.g. OR = 0.21, P < 0.001; OR = 2.78, P = 0.04). The majority of health professionals would inform patients about the mosaicism to facilitate informed decision making. The factor that health professionals identified as most important when discussing the transfer of mosaic embryos was the specific chromosome involved. Different self-rated competencies were found among health professionals with different backgrounds. Geneticists and genetic counsellors had the highest self-rated competencies. CONCLUSIONS: Most health professionals were willing to discuss the mosaicism in the embryo with patients to facilitate informed decision making. However, health professionals' uncertainty towards the transfer of mosaic embryos indicated a lack of a standardized transfer policy. In addition, obstetricians, gynaecologists and those with multiprofessional backgrounds showed deficiencies in several self-rated competencies, suggesting that education targeted to these groups is needed to optimize the quality of care of women considering transfer of mosaic embryos.

Should genes for non-syndromic hearing loss be included in reproductive genetic carrier screening: Views of people with a personal or family experience of deafness.

Many commercial reproductive genetic carrier screening (RGCS) panels include genes associated with non-syndromic hearing loss (NSHL), however little is known about the general acceptability of their inclusion. Although some couples wish to avoid having a deaf child, there are effective interventions and supports available for deafness, and no consensus on whether it is appropriate to reproductively screen NSHL genes. This study explored views of people with personal experience of deafness regarding carrier screening for genes associated with NSHL. We interviewed 27 participants; 14 who identified as deaf and 13 hearing parents of a deaf child. Thematic analysis was undertaken on transcripts of interviews. The findings reveal the complexity of attitudes within these groups. Some vacillated between the wish to support prospective parents' reproductive autonomy and concerns about potential harms, especially the expression of negative messages about deafness and the potential loss of acceptance in society. While some participants felt carrier screening could help prospective parents to prepare for a deaf child, there was little support for reproductive screening and termination of pregnancy. Participants emphasized the need for accurate information about the lived experience of deafness. The majority felt deafness is not as severe as other conditions included in RGCS, and most do not consider deafness as a disability. People with personal experience of deafness have diverse attitudes towards RGCS for deafness informed by their own identify and experience, and many have concerns about how it should be discussed and implemented in a population wide RGCS program.

A functional platform for the selection of pathogenic variants of PMM2 amenable to rescue via the use of pharmacological chaperones.

Different strategies are being investigated for treating PMM2-CDG, the most common congenital disorder of glycosylation. The use of pharmacochaperones (PCs) is one of the most promising. The present work characterizes the expression, stability, and enzymatic properties of 15 previously described clinical variants of the PMM2 protein, four novel variants, the Pmm2 mouse variant p.Phe115Leu, and its p.Phe119Leu human counterpart, with the aim of extending the potential use of pharmacochaperoning treatment. PMM2 variants were purified as stable homodimers, except for p.Asp65Gly, p.Ile120Thr, and p.Thr237Lys (no expression detected), p.Thr226Ser and p.Val231Met (aggregates), and p.Glu93Ala, p.Phe119Leu, and p.Phe115Leu (partial dissociated). Enzyme activity analyses identified severe variants and milder ones. Pure dimeric mutant proteins showed a reduction in thermal stability except for p.Asn216Asp. The thermal stability of all the unstable mutants was recovered in the presence of the PC compound VIII. This study adds to the list of destabilizing human variants amenable to rescue by small chemical compounds that increase the stability/activity of PMM2. The proposed platform can be reliably used for assessing the disease-causing effects of PMM2 missense variants, for assessing the correlation between genotype and phenotype, for confirming new clinical defects, and for identifying destabilizing mutations amenable to rescue by PCs.

De Novo Variants Disrupting the HX Repeat Motif of ATN1 Cause a Recognizable Non-Progressive Neurocognitive Syndrome.

Polyglutamine expansions in the transcriptional co-repressor Atrophin-1, encoded by ATN1, cause the neurodegenerative condition dentatorubral-pallidoluysian atrophy (DRPLA) via a proposed novel toxic gain of function. We present detailed phenotypic information on eight unrelated individuals who have de novo missense and insertion variants within a conserved 16-amino-acid "HX repeat" motif of ATN1. Each of the affected individuals has severe cognitive impairment and hypotonia, a recognizable facial gestalt, and variable congenital anomalies. However, they lack the progressive symptoms typical of DRPLA neurodegeneration. To distinguish this subset of affected individuals from the DRPLA diagnosis, we suggest using the term CHEDDA (congenital hypotonia, epilepsy, developmental delay, digit abnormalities) to classify the condition. CHEDDA-related variants alter the particular structural features of the HX repeat motif, suggesting that CHEDDA results from perturbation of the structural and functional integrity of the HX repeat. We found several non-homologous human genes containing similar motifs of eight to 10 HX repeat sequences, including RERE, where disruptive variants in this motif have also been linked to a separate condition that causes neurocognitive and congenital anomalies. These findings suggest that perturbation of the HX motif might explain other Mendelian human conditions.

Whole genome sequencing in transposition of the great arteries and associations with clinically relevant heart, brain and laterality genes.

BACKGROUND: The most common cyanotic congenital heart disease (CHD) requiring management as a neonate is transposition of great arteries (TGA). Clinically, up to 50% of TGA patients develop some form of neurodevelopmental disability (NDD), thought to have a significant genetic component. A "ciliopathy" and links with laterality disorders have been proposed. This first report of whole genome sequencing in TGA, sought to identify clinically relevant variants contributing to heart, brain and laterality defects. METHODS: Initial whole genome sequencing analyses on 100 TGA patients focussed on established disease genes related to CHD (n = 107), NDD (n = 659) and heterotaxy (n = 74). Single variant as well as copy number variant analyses were conducted. Variant pathogenicity was assessed using the American College of Medical Genetics and Genomics-Association for Molecular Pathology guidelines. RESULTS: Fifty-five putatively damaging variants were identified in established disease genes associated with CHD, NDD and heterotaxy; however, no clinically relevant variants could be attributed to disease. Notably, case-control analyses identified significantly more predicted-damaging, silent and total variants in TGA cases than healthy controls in established CHD genes (P < .001), NDD genes (P < .001) as well as across the three gene panels (P < .001). CONCLUSION: We present compelling evidence that the majority of TGA is not caused by monogenic rare variants and is most likely oligogenic and/or polygenic in nature, highlighting the complex genetic architecture and multifactorial influences on this CHD sub-type and its long-term sequelae. Assessment of variant burden in key heart, brain and/or laterality genes may be required to unravel the genetic contributions to TGA and related disabilities.

The views of people with a lived experience of deafness and the general public regarding genetic testing for deafness in the reproductive setting: A systematic review.

PURPOSE: Genes associated with nonsyndromic hearing loss are commonly included in reproductive carrier screening panels, which are now routinely offered in preconception and prenatal care in many countries. However, there is debate whether hearing loss should be considered a medical condition appropriate for screening. This systematic review assessed research on opinions of those with a lived experience of deafness and the general public regarding genetic testing for deafness in the reproductive setting. METHODS: Search of 5 online databases yielded 423 articles, 20 of which met inclusion criteria. We assessed the quality of each study, extracted data, and performed thematic analysis on qualitative studies. RESULTS: Most studies indicated interest in the use of prenatal diagnosis for deafness. However, there were mixed views, and sometimes strongly held views, expressed regarding the reproductive options that should be available to those with an increased chance of having a child with deafness. Studies were small, from a limited number of countries, and most were too old to include views regarding preimplantation genetic testing. CONCLUSION: There is a broad range of views regarding the use of reproductive options for deafness. Further research is essential to explore the benefits and harms of including nonsyndromic hearing loss genes in carrier screening.

Standardized practices for RNA diagnostics using clinically accessible specimens reclassifies 75% of putative splicing variants.

PURPOSE: Genetic variants causing aberrant premessenger RNA splicing are increasingly being recognized as causal variants in genetic disorders. In this study, we devise standardized practices for polymerase chain reaction (PCR)-based RNA diagnostics using clinically accessible specimens (blood, fibroblasts, urothelia, biopsy). METHODS: A total of 74 families with diverse monogenic conditions (31% prenatal-congenital onset, 47% early childhood, and 22% teenage-adult onset) were triaged into PCR-based RNA testing, with comparative RNA sequencing for 19 cases. RESULTS: Informative RNA assay data were obtained for 96% of cases, enabling variant reclassification for 75% variants that can be used for genetic counseling (71%), to inform clinical care (32%) and prenatal counseling (41%). Variant-associated mis-splicing was highly reproducible for 28 cases with samples from ≥2 affected individuals or heterozygotes and 10 cases with ≥2 biospecimens. PCR amplicons encompassing another segregated heterozygous variant was vital for clinical interpretation of 22 of 79 variants to phase RNA splicing events and discern complete from partial mis-splicing. CONCLUSION: RNA diagnostics enabled provision of a genetic diagnosis for 64% of recruited cases. PCR-based RNA diagnostics has capacity to analyze 81.3% of clinically significant genes, with long amplicons providing an advantage over RNA sequencing to phase RNA splicing events. The Australasian Consortium for RNA Diagnostics (SpliceACORD) provide clinically-endorsed, standardized protocols and recommendations for interpreting RNA assay data.

De Novo ZMYND8 variants result in an autosomal dominant neurodevelopmental disorder with cardiac malformations.

PURPOSE: ZMYND8 encodes a multidomain protein that serves as a central interactive hub for coordinating critical roles in transcription regulation, chromatin remodeling, regulation of super-enhancers, DNA damage response and tumor suppression. We delineate a novel neurocognitive disorder caused by variants in the ZMYND8 gene. METHODS: An international collaboration, exome sequencing, molecular modeling, yeast two-hybrid assays, analysis of available transcriptomic data and a knockdown Drosophila model were used to characterize the ZMYND8 variants. RESULTS: ZMYND8 variants were identified in 11 unrelated individuals; 10 occurred de novo and one suspected de novo; 2 were truncating, 9 were missense, of which one was recurrent. The disorder is characterized by intellectual disability with variable cardiovascular, ophthalmologic and minor skeletal anomalies. Missense variants in the PWWP domain of ZMYND8 abolish the interaction with Drebrin and missense variants in the MYND domain disrupt the interaction with GATAD2A. ZMYND8 is broadly expressed across cell types in all brain regions and shows highest expression in the early stages of brain development. Neuronal knockdown of the DrosophilaZMYND8 ortholog results in decreased habituation learning, consistent with a role in cognitive function. CONCLUSION: We present genomic and functional evidence for disruption of ZMYND8 as a novel etiology of syndromic intellectual disability.

The relationship between beta-ureidopropionase deficiency due to UPB1 variants and human phenotypes is uncertain.

BACKGROUND: Beta-ureidopropionase deficiency, caused by variants in UPB1, has been reported in association with various neurodevelopmental phenotypes including intellectual disability, seizures and autism. AIM: We aimed to reassess the relationship between variants in UPB1 and a clinical phenotype. METHODS: Literature review, calculation of carrier frequencies from population databases, long-term follow-up of a previously published case and reporting of additional cases. RESULTS: Fifty-three published cases were identified, and two additional cases are reported here. Of these, 14 were asymptomatic and four had transient neurological features; clinical features in the remainder were variable and included non-neurological presentations. Several of the variants previously reported as pathogenic are present in population databases at frequencies higher than expected for a rare condition. In particular, the variant most frequently reported as pathogenic, p.Arg326Gln, is very common among East Asians, with a carrier frequency of 1 in 19 and 1 in 907 being homozygous for the variant in gnomAD v2.1.1. CONCLUSION: Pending the availability of further evidence, UPB1 should be considered a 'gene of uncertain clinical significance'. Caution should be used in ascribing clinical significance to biochemical features of beta-ureidopropionase deficiency and/or UPB1 variants in patients with neurodevelopmental phenotypes. UPB1 is not currently suitable for inclusion in gene panels for reproductive genetic carrier screening. SYNOPSIS: The relationship between beta-ureidopropionase deficiency due to UPB1 variants and clinical phenotypes is uncertain.

Factors influencing patients' decision-making about preimplantation genetic testing for monogenic disorders.

STUDY QUESTION: What are the roles of individual and interpersonal factors in couples' decision-making regarding preimplantation genetic testing for monogenic disorders (PGT-M)? SUMMARY ANSWER: Couples' decision-making regarding PGT-M was associated with individual and interpersonal factors, that is the perceived consistency of information received, satisfaction with information, self-efficacy (individuals' beliefs in their ability to make decisions), actual knowledge about PGT-M and social support from the partner. WHAT IS KNOWN ALREADY: Various factors have been shown to be associated with decision-making regarding PGT-M. However, PGT-M is experienced at an individual level, and to date, no studies have investigated the roles of the above-mentioned individual and interpersonal factors. STUDY DESIGN, SIZE, DURATION: This is a cross-sectional study with 279 participants. Participants were recruited through IVFAustralia, Sydney Children's Hospital and support groups from May 2020 to November 2021. PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants were women who had undergone or were considering PGT-M and their partners. Participants were recruited through IVFAustralia, Sydney Children's Hospital and support groups to complete online questionnaires. Decisional regret, decisional satisfaction and decisional conflict were measured as outcome variables. Multiple linear regressions were performed to examine the association between factors and outcome variables. Mann-Whitney U tests were performed to test the differences between participants who had undergone PGT-M and those who were considering PGT-M. MAIN RESULTS AND THE ROLE OF CHANCE: For couples who had undergone PGT-M, decisional regret was significantly negatively associated with perceived consistency of information received (ß = -0.26, P < 0.01), self-efficacy (ß = -0.25, P < 0.01) and actual knowledge about PGT-M (ß = -0.30, P < 0.001), while decisional satisfaction had positive association with satisfaction with information received (ß = 0.37, P < 0.001) and self-efficacy (ß = 0.24, P < 0.05). For couples who were considering PGT-M, decisional conflict was negatively associated with satisfaction with information received (ß = -0.56, P < 0.001). For females who had undergone PGT-M, decisional regret was negatively associated with social support from the partner (ß = -0.35, P < 0.05) in addition to perceived consistency of information received (ß = -0.24, P < 0.05). In this group, decisional satisfaction was positively associated with women's satisfaction with the information received (ß = 0.34, P < 0.01), social support from the partner (ß = 0.26, P < 0.05) and self-efficacy (ß = 0.25, P < 0.05). For females who were considering PGT-M, decisional conflict was negatively associated with satisfaction with the information received (ß = -0.43, P < 0.01) and social support from the partner (ß = -0.30, P < 0.05). This study also identified those aspects of PGT-M that couples felt most concerned about in relation to their decision-making, in particular safety issues such as short- or long-term health problems for the baby and potential harms to the embryos and the mother's health. The likelihood of getting pregnant and having a baby with a genetic condition being tested for were also important in couples' decision-making. LIMITATIONS, REASONS FOR CAUTION: This study assessed the concerns of couples about having a baby with a variety of genetic conditions. However, condition-specific issues might not be covered. Furthermore, social support from the partner was assessed among females only. Male participants' perceived social support from their partner and the association between mutual support and decision-making were not assessed due to the absence of dyadic data. WIDER IMPLICATIONS OF THE FINDINGS: Results highlight the importance of effective patient education on PGT-M and the need to provide high-quality and consistent information in the context of patient-centred care. Patients are likely to benefit from information that addresses their specific concerns in relation to PGT-M. From females' perspective, support from partners is essential, and partners should, therefore, be encouraged to participate in all stages of the decision-making process. Suggestions for future studies were made. STUDY FUNDING/COMPETING INTEREST(S): B.M. was funded through a Senior Research Fellowship Level B (ID 1078523) from the National Health and Medical Research Council of Australia. L.C. was supported by a University International Postgraduate Award under the Australian Government Research Training Program (RTP) scholarship. No other funding was received for this study. The authors report no competing interests. TRIAL REGISTRATION NUMBER: N/A.

Decisional needs of patients considering preimplantation genetic testing: a systematic review.

This systematic review reports on the needs and sources of support in patients' decision-making regarding the uptake of preimplantation genetic testing (PGT). Five databases were searched systematically to capture qualitative and quantitative studies. A total of 2336 studies were screened by title and abstract. Twelve studies met the eligibility criteria and reported on 4047 participants. This systematic review shows that patients need information directly relevant to PGT treatment, and information on health care relating to treatment and alternative reproductive options. Information that is too detailed, excessive and contains a large volume of medical terminology can be a barrier to decision-making. Published research suggests that health professionals provide general information on PGT and discuss it in detail only when patients require more information about it. Additionally, studies have shown that patients receive decisional support through mass media, significant persons in their lives and health professionals, whereas referring obstetricians and gynaecologists provided relatively less help compared with other health professionals. This systematic review highlights the importance of developing decision aids that meet patients' decisional needs as indicated in previous studies and that use innovative formats to deliver information. Additionally, given rapid technical developments, a dearth of continuing professional education is available on PGT for clinicians to keep updated.

Reproductive genetic carrier screening and inborn errors of metabolism: The voice of the inborn errors of metabolism community needs to be heard.

Reproductive genetic carrier screening (RGCS) has a history spanning more than 50 years, but for most of that time has been limited to screening for one or a few conditions in targeted population groups. The advent of massively parallel sequencing has led to rapid growth in screening for panels of up to hundreds of genes. Such panels typically include numerous genes associated with inborn errors of metabolism (IEM). There are considerable potential benefits for families from screening, but there are also risks and potential pitfalls. The IEM community has a vital role to play in guiding gene selection and assisting with the complexities that arise from screening, including interpreting complex biochemical assays and counselling at-risk couples about phenotypes and treatments.

Views of reproductive genetic carrier screening participants regarding screening for genes associated with non-syndromic hearing loss.

OBJECTIVE: Reproductive genetic carrier screening (RGCS) panels often include genes associated with non-syndromic hearing loss (NSHL) despite a lack of evidence of acceptability. Although some couples take steps to avoid having a child who is deaf, there are effective interventions for children who are deaf. There is no consensus whether deafness is considered a disabling condition. METHOD: This study explored views of people who had RGCS, without genes for NSHL, about this topic. Online surveys were sent to 2186 people who had a low chance RGCS result and 655 completed the survey (participation rate 30%). RESULTS: Sixty-three percent (N = 412) think deafness is a serious health condition. The majority agreed (60%, N = 391) that with support (i.e. hearing aids/cochlear implants) deafness is a minor condition in children. Most (84%, N = 545) agreed genes for NSHL should be included in RGCS. Thirty-five percent (N = 231) indicated they would make different reproductive decisions if they had an increased chance of having a child born deaf; 31% would not change their reproductive plans and 34% were unsure what they would do. CONCLUSION: While the majority support inclusion of genes associated with NSHL in RGCS, there was uncertainty about the severity of deafness as a health condition and there was no consensus on whether it is a health condition that warrants changing reproductive decisions.

Paediatric genomic testing: Navigating genomic reports for the general paediatrician.

Monogenic rare disorders contribute significantly to paediatric morbidity and mortality, and elucidation of the underlying genetic cause may have benefits for patients, families and clinicians. Advances in genomic technology have enabled diagnostic yields of up to 50% in some paediatric cohorts. This has led to an increase in the uptake of genetic testing across paediatric disciplines. This can place an increased burden on paediatricians, who may now be responsible for interpreting and explaining test results to patients. However, genomic results can be complex, and sometimes inconclusive for the ordering paediatrician. Results may also cause uncertainty and anxiety for patients and their families. The paediatrician's genetic literacy and knowledge of genetic principles are therefore critical to inform discussions with families and guide ongoing patient care. Here, we present four hypothetical case vignettes where genomic testing is undertaken, and discuss possible results and their implications for paediatricians and families. We also provide a list of key terms for paediatricians.

Pathogenic variants in CDH11 impair cell adhesion and cause Teebi hypertelorism syndrome.

Teebi hypertelorism syndrome (THS; OMIM 145420) is a rare craniofacial disorder characterized by hypertelorism, prominent forehead, short nose with broad or depressed nasal root. Some cases of THS have been attributed to SPECC1L variants. Homozygous variants in CDH11 truncating the transmembrane and intracellular domains have been implicated in Elsahy-Waters syndrome (EWS; OMIM 211380) with hypertelorism. We report THS due to CDH11 heterozygous missense variants on 19 subjects from 9 families. All affected residues in the extracellular region of Cadherin-11 (CHD11) are highly conserved across vertebrate species and classical cadherins. Six of the variants that cluster around the EC2-EC3 and EC3-EC4 linker regions are predicted to affect Ca2+ binding that is required for cadherin stability. Two of the additional variants [c.164G > C, p.(Trp55Ser) and c.418G > A, p.(Glu140Lys)] are also notable as they are predicted to directly affect trans-homodimer formation. Immunohistochemical study demonstrates that CDH11 is strongly expressed in human facial mesenchyme. Using multiple functional assays, we show that five variants from the EC1, EC2-EC3 linker, and EC3 regions significantly reduced the cell-substrate trans adhesion activity and one variant from EC3-EC4 linker results in changes in cell morphology, focal adhesion, and migration, suggesting dominant negative effect. Characteristic features in this cohort included depressed nasal root, cardiac and umbilical defects. These features distinguished this phenotype from that seen in SPECC1L-related hypertelorism syndrome and CDH11-related EWS. Our results demonstrate heterozygous variants in CDH11, which decrease cell-cell adhesion and increase cell migratory behavior, cause a form of THS, as termed CDH11-related THS.