Elizabeth Wall

KBG syndrome is one of the most frequent neurodevelopmental disorders and is caused by ANKRD11 variants. Postnatal short stature is observed in ~50% of patients. Recombinant human growth hormone (rhGH) has become a valuable treatment for patients with growth hormone deficiency (GHD) along with Prader–Willi and Turner syndrome. Limited evidence suggests benefits for some patients with KBG syndrome, but systematic analysis and detailed phenotyping are lacking. In this study, we include six unpublished patients with KBG syndrome treated with rhGH and 22 patients from the literature. At treatment start, 43% had GHD. Median height before treatment was −2.9 standard deviation score (SDS) which increased to −1.8 SDS at the latest measurement. Moreover, half of the patients showed height gains of ≥ 1 SDS and 10/18 patients with short stature before treatment achieved heights within normal ranges following treatment or at the latest available measurement. Of interest, the difference between pre‐treatment height SDS and that at the latest measurement (∆HSDS) was comparable for patients with and without GHD. This study represents the largest group of patients with KBG syndrome treated with rhGH so far and suggests that rhGH treatment has a positive impact on height, as indicated by ∆HSDS, in a subset of patients.

Objective: In the West Midlands regional genetics service, cases of perinatal death with a possible genetic diagnosis are evaluated by the perinatal pathology genetic multidisciplinary team (MDT). The MDT assesses autopsy findings and suggests appropriate genomic assessment. The objective of this retrospective service evaluation was to determine the clinical utility of the MDT in assessing perinatal deaths associated with structural anomaly. This is the first evaluation since the introduction of whole‐genome and whole‐exome sequencing in routine clinical care.Methods: This was a retrospective service evaluation including all cases of perinatal death with an associated structural anomaly and suspected genetic etiology that underwent perinatal MDT assessment between January and December 2021. All cases received a full or partial postmortem examination and at least a chromosomal microarray analysis. Demographic characteristics, phenotype, genotype, MDT recommendations, diagnoses, outcomes and impact of postmortem analysis and genetic testing data were collected from patient case notes.Results: Overall, 123 cases were discussed at the MDT meetings in 2021. Genetic evaluation was recommended in 84 cases and accepted in 64 cases. A range of genetic tests were requested according to indication and availability. Thirty diagnoses were made in 29 cases from 26 unrelated families. The diagnostic yield was 24% (29/123) in all cases or 45% (29/64) in cases with a suspected genetic diagnosis who underwent genetic testing. Postmortem examination provided clinically actionable phenotypic data in 79% of cases. A genetic diagnosis enabled accurate recurrence risk counseling and provision of appropriate follow‐up, including prenatal testing and preimplantation diagnosis for patients with inherited conditions.Conclusions: Genomic testing was a clinically useful addition to (but not a substitute for) postmortem examination in cases of perinatal death associated with structural anomaly. The MDT approach helped assess cases and plan appropriate follow‐up. Expedited whole‐genome sequencing or panel‐agnostic analysis were most appropriate for heterogeneous presentations. This broad approach can also expand knowledge of prenatal phenotypes and detect novel disease genes, and should be a priority in future research. © 2024 International Society of Ultrasound in Obstetrics and Gynecology.

We report two male fetuses born to a healthy unrelated couple, with agenesis of the corpus callosum identified on detailed 20‐week ultrasound scans and confirmed by in‐utero MRI. Whole‐genome sequencing identified a likely pathogenic missense variant in the CLCN4 gene, establishing this as the causative gene in the family. Pathogenic variants in the CLCN4 gene cause a neurodevelopmental disorder (also called Raynaud‐Claes syndrome) inherited in an X‐linked pattern. The disorder is characterised by developmental delay, intellectual disability, autism spectrum disorder, epilepsy, mental health conditions, and significant feeding difficulties, predominantly, but not exclusively, affecting males. This is the first report of a prenatal phenotype associated with variants in the CLCN4 gene. The diagnosis of the CLCN4‐related neurodevelopmental disorder in this family allowed accurate genetic counseling and discussion of reproductive choices. This leaves uncertainty about the possibility of a postnatal neurodevelopmental phenotype in heterozygous females, which we discuss.

We report a fetus with hydrops, congenital heart disease and bilateral radioulnar synostosis caused by a novel pathogenic MECOM variant. The female fetus was referred for post‐mortem examination after fetal hydrops and intrauterine death was diagnosed at 20 weeks gestation. Post‐mortem examination confirmed fetal hydrops, pallor, truncus arteriosus and bilateral radioulnar synostosis. Trio whole genome sequencing analysis detected a novel de novo heterozygous pathogenic loss‐of‐function variant in MECOM (NM_004991), associated with a diagnosis of Radioulnar Synostosis with Amegakaryocytic Thrombocytopenia 2 (RUSAT‐2). RUSAT‐2 is a variable condition associated postnatally with bone marrow failure, radioulnar synostosis and congenital anomalies. RUSAT‐2 is not currently associated with a prenatal phenotype or fetal demise, and was not present on diagnostic NHS prenatal gene panels at time of diagnosis. This case highlights the diagnostic value of detailed phenotyping with post‐mortem examination, and of using a broad sequencing approach.