DYRK1B haploinsufficiency in a family with metabolic syndrome and abnormal cognition.

A family with DYRK1B LOF variant offering to expand the phenotype beyond the metabolic syndrome.

The prevalence of prenatal sonographic findings in postnatal diagnostic exome sequencing performed for neurocognitive phenotypes: A cohort study.

OBJECTIVE: Prenatal exome sequencing (ES) is currently indicated for fetal malformations. Some neurocognitive genetic disorders may not have a prenatal phenotype. We assessed the prevalence of prenatally detectable phenotypes among patients with neurocognitive syndromes diagnosed postnatally by ES. METHODS: The medical files of a cohort of 138 patients diagnosed postnatally with a neurocognitive disorder using ES were reviewed for prenatal sonographic data. The Online Mendelian Inheritance in Man (OMIM) database was searched for prenatally detectable phenotypes for all genes identified. RESULTS: Prenatal imaging data were available for 122 cases. Of these, 29 (23.75%) had fetal structural abnormalities and another 29 had other ultrasound abnormalities (fetal growth restriction, polyhydramnios, elevated nuchal translucency). In 30 patients, structural aberrations that were not diagnosed prenatally were detected at birth; in 21 (17.2%), the abnormalities could theoretically be detected prenatally by third-trimester/targeted scans. According to OMIM, 55.9% of the diagnosed genes were not associated with structural anomalies. CONCLUSIONS: Most patients (52.5%) with postnatally diagnosed neurocognitive disorders did not have prenatal sonographic findings indicating prenatal ES should be considered. The prevalence of specific prenatal phenotypes such as fetal growth restriction and polyhydramnios in our cohort suggests that additional prenatal findings should be assessed as possible indications for prenatal ES.

When phenotype does not match genotype: importance of "real-time" refining of phenotypic information for exome data interpretation.

PURPOSE: Clinical data provided to genetic testing laboratories are frequently scarce. Our purpose was to evaluate clinical scenarios where phenotypic refinement in proband's family members might impact exome data interpretation. METHODS: Of 614 exomes, 209 were diagnostic and included in this study. Phenotypic information was gathered by the variant interpretation team from genetic counseling letters and images. If a discrepancy between reported clinical findings and presumably disease-causing variant segregation was observed, referring clinicians were contacted for phenotypic clarification. RESULTS: In 16/209 (7.7%) cases, phenotypic refinement was important due to (1) lack of cosegregation of disease-causing variant with the reported phenotype; (2) identification of different disorders with overlapping symptoms in the same family; (3) similar features in proband and family members, but molecular cause identified in proband only; and (4) previously unrecognized maternal condition causative of child's phenotype. As a result of phenotypic clarification, in 12/16 (75%) cases definition of affected versus unaffected status in one of the family members has changed, and in one case variant classification has changed. CONCLUSION: Detailed description of phenotypes in family members including differences in clinical presentations, even if subtle, are important in exome interpretation and should be communicated to the variant interpretation team.

The diagnostic efficacy of exome data analysis using fixed neurodevelopmental gene lists: Implications for prenatal setting.

OBJECTIVE: Laboratories performing prenatal exome sequencing (ES) frequently limit analysis to predetermined gene lists. We used a diagnostic postnatal ES cohort to assess how many of the genes diagnosed are not included in a number of select fixed lists used for prenatal diagnosis. METHODS: Of 601 postnatal ES tests, pathogenic variants related to neurodevelopmental disorders were detected in 138 probands. We evaluated if causative genes were present in the following: (1) Developmental Disorders Genotype-Phenotype database list, (2) a commercial laboratory list for prenatal ES, (3) the PanelApp fetal anomalies panel, and (4) a published list used for prenatal diagnosis by ES (Prenatal Assessment of Genomes and Exomes study). RESULTS: The percentages of cases where the diagnosed gene was not included in the selected four lists were; 11.6%, 17.24%, 23.2%, and 10.9%, respectively. In 13/138 (9.4%) cases, the causative gene was not included in any of the lists; in 4/13 (∼30%) cases noninclusion was explained by a relatively recent discovery of gene-phenotype association. CONCLUSIONS: A significant number of genes related to neurocognitive phenotypes are not included in some of the lists used for prenatal ES data interpretation. These are not only genes related to recently discovered disorders, but also genes with well-established gene-phenotype.

The Diagnostic Yield and Implications of Targeted Founder Pathogenic Variant Testing in an Israeli Cohort.

Founder pathogenic variants (PVs) are prevalent in Israel. This study investigated the current practice of offering cancer patients two-step genetic testing, starting with targeted testing for recurring founder PVs, followed, if negative, by next-generation sequencing. A total of 2128 subjects with cancer or a positive family history underwent oncogenetic testing with a panel of 51 recurring PVs at a tertiary medical center in March 2020-January 2023. Those with a known familial PV (n = 370) were excluded from the analysis. Among the remainder, 128/1758 (7%) were heterozygous for at least one variant, and 44 (34%) carried a PV of medium-high penetrance (MHPV). Cancer was diagnosed in 1519/1758 patients (86%). The diagnostic yield of founder MHPV testing was 2% in cancer patients and 4% in healthy individuals with a positive family history. It was higher in Ashkenazi Jews than non-Ashkenazi Jews and Arabs, but not over 10% for any type of cancer, and it was significantly higher in younger (<40 years) than older (>50 years) individuals (7% vs. 1%). Eighty-four of the heterozygotes (66%), mostly Ashkenazi Jews, harbored a low-penetrance variant (LPV) not associated with the diagnosed cancer, usually APC c.3902T>A. These findings question the advantage of two-step testing. LPVs should not be included in targeted testing because this can lead to an overestimation of the yield, and their detection does not preclude further comprehensive testing.