Further validation and psychometric properties of the Spanish adaptation of the Genetic Counseling Outcome Scale

Evaluation of clinical genetic services is challenging due to the nature of their interventions. The Genetic Counseling Outcome Scale (GCOS-24), a patient-reported outcome measure, was developed to measure empowerment, an important patient-reported outcome from genetic counseling. Previously, we translated and adapted GCOS-24 for use in Spain, but neither test–retest reliability nor structural and construct validity were assessed at that time. In the present study, we set out to test the reliability and validity of the Spanish adaptation of the GCOS-24 against already validated Spanish language measures of satisfaction with life, anxiety, and health locus of control. 880 patients/families who attended the genetics clinic were invited to participate in a online survey. 201 participants (23%) completed the four questionnaires at the first timepoint, and 59 of these (29%) completed GCOS-24 again the second timepoint, 2–4 weeks later. Test–retest reliability was confirmed, with no significant differences between responses to GCOS-24 at the first and second timepoints and good internal consistency. Convergent validity was confirmed between GCOS-24 and measures of satisfaction with life and anxiety but not with measures of health locus of control. For the structural and construct validation, an exploratory factor analysis was performed. The resulting factorial structure of GCOS-24 consists of 6 factors that accumulate 68% of the variance shared by the 21 items that remained in the model. We applied the factor structure of the three validated measures to the available data and analyzed the correlation between factors of GCOS-24 and the other scales. The results showed significant and consistent correlation with factors of the satisfaction with life and anxiety scales but no significant correlation with internal health locus of control. The use of the Spanish adaptation of GCOS-24 in other genetic clinics in Spain will help to validate it further. This study contributes to the international validation of GCOS-24 to evaluate the quality of genetic counseling in Europe

Loss-of-function of the Zinc Finger Homeobox 4 (ZFHX4) gene causes a novel neurodevelopmental disorder

Neurodevelopmental disorders (NDDs) result from impaired development and functioning of the brain. Here, we identify a novel NDD caused by loss-of-function variation in ZFHX4, encoding a zinc-finger homeodomain transcription factor. In 2011, ZFHX4 haploinsufficiency was suggested as (one of) the underlying mechanism(s) in 8q21.11 microdeletions. Moreover, in 2020, ZFHX4 was reported as a novel NDD candidate gene in a large-scale exome-sequencing study. Through an international collaboration, we gathered data on 47 individuals with protein truncating variants (n=27), (micro)deletions (n=19) or an inversion (n=1) affecting ZFHX4. Loss-of-function of ZFHX4 consistently associates with ID, morphological abnormalities of the central nervous system, short stature, hypotonia and distinctive facial characteristics as supported by artificial intelligence (Face2Gene), and, occasionally, cleft palate and anterior segment dysgenesis. We identified a preliminary mild common DNA methylation profile in leukocyte-derived DNA of patients with truncating variants and with (micro)deletions affecting ZFHX4. Via data-mining and multiple in vitro models we identified ZFHX4 as a nuclear protein and found increasing expression during human brain development and neuronal differentiation. First-generation (F0) zfhx4 crispant zebrafish - (mosaic) mutant for zfhx4 loss-of-function variants - have significantly smaller Meckel’s cartilages and ethmoid plates in comparison with control zebrafish upon Alcian blue staining. To get a better understanding of its role during neurodevelopment, we are currently assessing the interaction partners and downstream targets of ZFHX4 in neural progenitor cells and neural crest cells. In conclusion, ZFHX4 appears to be essential for neural and craniofacial development and ZFHX4 loss-of-function variants are associated with a novel form of syndromic ID

Loss-of-function of the Zinc Finger Homeobox 4 (ZFHX4) gene causes a novel neurodevelopmental disorder

Neurodevelopmental disorders (NDDs) result from impaired development and functioning of the brain. Here, we identify a novel NDD caused by loss-of-function variation in ZFHX4, encoding a zinc-finger homeodomain transcription factor. In 2011, ZFHX4 haploinsufficiency was suggested as (one of) the underlying mechanism(s) in 8q21.11 microdeletions. Moreover, in 2020, ZFHX4 was reported as a novel NDD candidate gene in a large-scale exome-sequencing study. Through an international collaboration, we gathered data on 47 individuals with protein truncating variants (n=27), (micro)deletions (n=19) or an inversion (n=1) affecting ZFHX4. Loss-of-function of ZFHX4 consistently associates with ID, morphological abnormalities of the central nervous system, short stature, hypotonia and distinctive facial characteristics as supported by artificial intelligence (Face2Gene), and, occasionally, cleft palate and anterior segment dysgenesis. We identified a preliminary mild common DNA methylation profile in leukocyte-derived DNA of patients with truncating variants and with (micro)deletions affecting ZFHX4. Via data-mining and multiple in vitro models we identified ZFHX4 as a nuclear protein and found increasing expression during human brain development and neuronal differentiation. First-generation (F0) zfhx4 crispant zebrafish - (mosaic) mutant for zfhx4 loss-of-function variants - have significantly smaller Meckel’s cartilages and ethmoid plates in comparison with control zebrafish upon Alcian blue staining. To get a better understanding of its role during neurodevelopment, we are currently assessing the interaction partners and downstream targets of ZFHX4 in neural progenitor cells and neural crest cells. In conclusion, ZFHX4 appears to be essential for neural and craniofacial development and ZFHX4 loss-of-function variants are associated with a novel form of syndromic ID

Loss-of-function of the Zinc Finger Homeobox 4 (ZFHX4) gene underlies a neurodevelopmental disorder

The 8q21.11 microdeletions encompassing the transcription factor ZFHX4, have been associated with a syndromic form of intellectual disability, hypotonia, decreased balance and hearing loss. Here, we report on 55 individuals with protein truncating variants (n=34), (micro)deletions (n=20) or an inversion (n=1) affecting ZFHX4 with variable developmental delay and intellectual disability (85%), distinctive facial characteristics, morphological abnormalities of the central nervous system, short stature, hypotonia, and occasionally cleft palate and anterior segment dysgenesis. The phenotypes associated with the 8q21.11 microdeletions and ZFHX4 intragenic loss of function variants largely overlap identifying ZFHX4 as the main driver for the microdeletion syndrome, although leukocyte-derived DNA shows a mild common methylation profile in (micro)deletions patients only. We identified ZFHX4 as a nuclear protein that is increasingly expressed during human brain development and neuronal differentiation. In neural progenitor cells, ZFHX4 interacting factors suggest an important role for ZFHX4 in cellular and tissue developmental pathways, especially during embryonic and neural development. Accordingly, we observed that ZFHX4 interacts with the promoter regions of genes with crucial roles in embryonic, neuron and axon development. Since ZFHX4 loss-of-function associates with consistent dysmorphic features, we investigated whether the disruption of zfhx4 causes craniofacial abnormalities in zebrafish. First-generation (F0) zfhx4 crispant zebrafish, (mosaic) mutant for zfhx4 loss-of-function variants, have significantly smaller Meckel’s cartilages and ethmoid plates compared to control zebrafish. Furthermore, behavioral assays showed a decreased movement frequency in the zfhx4 crispant zebrafish in comparison with control zebrafish larvae. Our in vivo work for zfhx4 suggests a role for facial skeleton patterning, palatal and neurodevelopment

Loss-of-function of the Zinc Finger Homeobox 4 (<i>ZFHX4</i>) gene underlies a neurodevelopmental disorder

Abstract8q21.11 microdeletions encompassing the gene encoding transcription factor ZFHX4, have previously been associated by us with a syndromic form of intellectual disability, hypotonia, decreased balance and hearing loss. Here, we report on 57 individuals, 52 probands and 5 affected family members, with protein truncating variants (n=36), (micro)deletions (n=20) or an inversion (n=1) affectingZFHX4with variable developmental delay and intellectual disability, distinctive facial characteristics, morphological abnormalities of the central nervous system, behavioral alterations, short stature, hypotonia, and occasionally cleft palate and anterior segment dysgenesis. The phenotypes associated with 8q21.11 microdeletions andZFHX4intragenic loss-of-function variants largely overlap, identifying ZFHX4 as the main driver for the microdeletion syndrome, although leukocyte-derived DNA shows a mild common methylation profile for (micro)deletions only. We identify ZFHX4 as a transcription factor that is increasingly expressed during human brain development and neuronal differentiation. Furthermore, ZFHX4 interacting factors identified via IP-MS in neural progenitor cells, suggest an important role for ZFHX4 in cellular and developmental pathways, especially during histone modifications, cytosolic transport and development. Additionally, using CUT&amp;RUN, we observed that ZFHX4 binds with the promoter regions of genes with crucial roles in embryonic, neuron and axon development. Since loss-of-function variants inZFHX4are found with consistent dysmorphic facial features, we investigated whether the disruption ofzfhx4causes craniofacial abnormalities in zebrafish. First-generation (F0)zfhx4crispant zebrafish, (mosaic) mutant forzfhx4loss-of-function variants, have significantly shorter Meckel’s cartilages and smaller ethmoid plates compared to control zebrafish. Furthermore, behavioral assays show a decreased movement frequency in thezfhx4crispant zebrafish in comparison with control zebrafish larvae. Although further research is needed, ourin vivowork suggests a role for zfhx4 in facial skeleton patterning, palatal development and behavior.</jats:p

Cancer risks by sex and variant type in PTEN hamartoma tumor syndrome.

BACKGROUND: PTEN Hamartoma Tumor Syndrome (PHTS) is a rare syndrome with a broad phenotypic spectrum, including increased risks of breast (BC, 67%-78% at age 60 years), endometrial (EC, 19%-28%), and thyroid cancer (TC, 6%-38%). Current risks are likely overestimated due to ascertainment bias. We aimed to provide more accurate and personalized cancer risks. METHODS: This was a European, adult PHTS cohort study with data from medical files, registries, and/or questionnaires. Cancer risks and hazard ratios were assessed with Kaplan-Meier and Cox regression analyses, and standardized incidence ratios were calculated. Bias correction consisted of excluding cancer index cases and incident case analyses. RESULTS: A total of 455 patients were included, including 50.5% index cases, 372 with prospective follow-up (median 6 years, interquartile range = 3-10 years), and 159 of 281 females and 39 of 174 males with cancer. By age 60 years, PHTS-related cancer risk was higher in females (68.4% to 86.3%) than males (16.4% to 20.8%). Female BC risks ranged from 54.3% (95% confidence interval [CI] = 43.0% to 66.4%) to 75.8% (95% CI = 60.7% to 88.4%), with two- to threefold increased risks for PTEN truncating and approximately twofold for phosphatase domain variants. EC risks ranged from 6.4% (95% CI = 2.1% to 18.6%) to 22.1% (95% CI = 11.6% to 39.6%) and TC risks from 8.9% (95% CI = 5.1% to 15.3%) to 20.5% (95% CI = 11.3% to 35.4%). Colorectal cancer, renal cancer, and melanoma risks were each less than 10.0%. CONCLUSIONS: Females have a different BC risk depending on their PTEN germline variant. PHTS patients are predominantly at risk of BC (females), EC, and TC. This should be the main focus of surveillance. These lower, more unbiased and personalized risks provide guidance for optimized cancer risk management

Cancer risks by sex and variant type in PTEN hamartoma tumor syndrome.

BACKGROUND: PTEN Hamartoma Tumor Syndrome (PHTS) is a rare syndrome with a broad phenotypic spectrum, including increased risks of breast (BC, 67%-78% at age 60 years), endometrial (EC, 19%-28%), and thyroid cancer (TC, 6%-38%). Current risks are likely overestimated due to ascertainment bias. We aimed to provide more accurate and personalized cancer risks. METHODS: This was a European, adult PHTS cohort study with data from medical files, registries, and/or questionnaires. Cancer risks and hazard ratios were assessed with Kaplan-Meier and Cox regression analyses, and standardized incidence ratios were calculated. Bias correction consisted of excluding cancer index cases and incident case analyses. RESULTS: A total of 455 patients were included, including 50.5% index cases, 372 with prospective follow-up (median 6 years, interquartile range = 3-10 years), and 159 of 281 females and 39 of 174 males with cancer. By age 60 years, PHTS-related cancer risk was higher in females (68.4% to 86.3%) than males (16.4% to 20.8%). Female BC risks ranged from 54.3% (95% confidence interval [CI] = 43.0% to 66.4%) to 75.8% (95% CI = 60.7% to 88.4%), with two- to threefold increased risks for PTEN truncating and approximately twofold for phosphatase domain variants. EC risks ranged from 6.4% (95% CI = 2.1% to 18.6%) to 22.1% (95% CI = 11.6% to 39.6%) and TC risks from 8.9% (95% CI = 5.1% to 15.3%) to 20.5% (95% CI = 11.3% to 35.4%). Colorectal cancer, renal cancer, and melanoma risks were each less than 10.0%. CONCLUSIONS: Females have a different BC risk depending on their PTEN germline variant. PHTS patients are predominantly at risk of BC (females), EC, and TC. This should be the main focus of surveillance. These lower, more unbiased and personalized risks provide guidance for optimized cancer risk management

Cancer risks by sex and variant type in PTEN Hamartoma Tumor Syndrome

BACKGROUND: PTEN Hamartoma Tumor Syndrome (PHTS) is a rare syndrome with a broad phenotypic spectrum, including increased risks of breast (BC, 67-78% at age 60), endometrial (EC, 19-28%) and thyroid cancer (TC, 6-38%). Current risks are likely overestimated due to ascertainment bias. We aimed to provide more accurate and personalized cancer risks. METHODS: A European, adult PHTS cohort study with data from medical files, registries and/or questionnaires. Cancer risks and hazard ratios were assessed with Kaplan-Meier and Cox regression analyses, and standardized incidence ratios (SIR) were calculated. Bias correction consisted of excluding cancer index cases and incident case analyses. RESULTS: 455 patients were included, including 50.5% index cases, 372 with prospective follow-up (median 6 year, IQR : 3-10), and 159/281 females and 39/174 males with cancer. By age 60, PHTS-related cancer risk was higher in females (68.4% to 86.3%) than males (16.4% to 20.8%). Female BC risks ranged from 54.3% (95%CI 43.0-66.4) to 75.8% (95%CI 60.7-88.4), with two-to-three-fold increased risks for PTEN truncating and about two-fold for phosphatase domain variants. EC risks ranged from 6.4% (95%CI 2.1-18.6) to 22.1% (95%CI 11.6-39.6), and TC risks from 8.9% (95%CI 5.1-15.3) to 20.5% (95%CI 11.3-35.4). Colorectal cancer, renal cancer and melanoma risks were each below 10.0%. CONCLUSION: Females have a different breast cancer risk depending on their PTEN germline variant. PHTS patients are predominantly at risk of breast (females), endometrial and thyroid cancer. This should be the main focus of surveillance. These lower, more unbiased and personalized risks provide guidance for optimized cancer risk management