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Moebius syndrome (MBS) is a congenital, non-progressive facial and abducens nerve palsy in the presence of full vertical gaze and may be associated with limb abnormalities and craniofacial dysmorphisms. MBS is now defined as a disorder of rhombencephalic maldevelopment and recent gene discoveries have shown this to be a dominant disorder in a subset of patients. Accurate diagnosis and management by a multidisciplinary team with expertise in congenital facial palsy is paramount.

IntroductionRecent evidence has emerged linking mutations in CDK13 to syndromic congenital heart disease. We present here genetic and phenotypic data pertaining to 16 individuals with CDK13 mutations.MethodsPatients were investigated by exome sequencing, having presented with developmental delay and additional features suggestive of a syndromic cause.ResultsOur cohort comprised 16 individuals aged 4–16 years. All had developmental delay, including six with autism spectrum disorder. Common findings included feeding difficulties (15/16), structural cardiac anomalies (9/16), seizures (4/16) and abnormalities of the corpus callosum (4/11 patients who had undergone MRI). All had craniofacial dysmorphism, with common features including short, upslanting palpebral fissures, hypertelorism or telecanthus, medial epicanthic folds, low-set, posteriorly rotated ears and a small mouth with thin upper lip vermilion. Fifteen patients had predicted missense mutations, including five identical p.(Asn842Ser) substitutions and two p.(Gly717Arg) substitutions. One patient had a canonical splice acceptor site variant (c.2898–1G>A). All mutations were located within the protein kinase domain of CDK13. The affected amino acids are highly conserved, and in silico analyses including comparative protein modelling predict that they will interfere with protein function. The location of the missense mutations in a key catalytic domain suggests that they are likely to cause loss of catalytic activity but retention of cyclin K binding, resulting in a dominant negative mode of action. Although the splice-site mutation was predicted to produce a stable internally deleted protein, this was not supported by expression studies in lymphoblastoid cells. A loss of function contribution to the underlying pathological mechanism therefore cannot be excluded, and the clinical significance of this variant remains uncertain.ConclusionsThese patients demonstrate that heterozygous, likely dominant negative mutations affecting the protein kinase domain of the CDK13 gene result in a recognisable, syndromic form of intellectual disability, with or without congenital heart disease.

Moebius syndrome is a collection of orofacial anomalies with highly variable features affecting many different systems but characterised by bilateral facial palsy and absent eye abduction. We largely regard Moebius syndrome as a diagnosis of exclusion. Lack of awareness and knowledge means that children often fall between services, leading to treatment delays and difficulty interfacing with social care and schools, with long-term impact on physical health and psychosocial development. We developed a multidisciplinary team comprising core clinicians (lead physician, geneticist, speech and language therapist, psychologist and specialist nurse) and an expanded group to encompass the other affected systems. The interactions between our specialties lead to the development of a treatment protocol, which we present. The protocol harnesses the aspects of care of children with a range of other rare diseases at a specialised paediatric centre and synthesises them into a holistic approach for MBS and related conditions. Management is sequenced on an “ABC-style” basis, with airway, feeding, vision and speech taking priority in the early years. We define management priorities as airway stabilisation with swallow assessment, ocular surface protection and maintenance of nutritional support. Management principles for issues such as speech, reflux, drooling and sleep issues are outlined. In later years, psychological support has a prominent role geared towards monitoring and interventions for low mood, self-esteem and bullying.

Background Greenberg dysplasia is a rare, autosomal recessive, prenatal lethal bone dysplasia caused by biallelic pathogenic variants in the lamin B receptor (LBR) gene. Pathogenic variants in LBR are also associated with Pelger–Huët anomaly, an autosomal dominant benign abnormality of the nuclear shape and chromatin organization of blood granulocytes, and Pelger–Huët anomaly with variable skeletal anomalies, a mild, regressing to moderate–severe autosomal recessive condition. Conditions with abnormal sterol metabolism and different genetic basis have clinical and radiographic features similar to Greenberg dysplasia, for example X‐linked dominant chondrodysplasia punctata, Conradi–Hünermann type, and CHILD syndrome, and other conditions with unknown genetic etiology display very similar features, for example, dappled diaphyseal dysplasia and Astley–Kendall dysplasia. Methods We present a fetus with typical clinical and radiographic features of Greenberg dysplasia, and review the literature. Results Genetic testing confirmed the diagnosis Greenberg dysplasia: homozygosity for a pathogenic variant in LBR. Conclusion Comparing the clinical and radiographic phenotypes of Greenberg dysplasia, dappled diaphyseal dysplasia, and Astley–Kendall dysplasia, we suggest that these are allelic disorders. Comparing the clinical and radiographic phenotypes of Greenberg dysplasia, dappled diaphyseal dysplasia, and Astley‐Kendall dysplasia, we suggest that these are allelic disorders.

Purpose Pathogenic variants in KAT6A have recently been identified as a cause of syndromic developmental delay. Within 2 years, the number of patients identified with pathogenic KAT6A variants has rapidly expanded and the full extent and variability of the clinical phenotype has not been reported. Methods We obtained data for patients with KAT6A pathogenic variants through three sources: treating clinicians, an online family survey distributed through social media, and a literature review. Results We identified 52 unreported cases, bringing the total number of published cases to 76. Our results expand the genotypic spectrum of pathogenic variants to include missense and splicing mutations. We functionally validated a pathogenic splice-site variant and identified a likely hotspot location for de novo missense variants. The majority of clinical features in KAT6A syndrome have highly variable penetrance. For core features such as intellectual disability, speech delay, microcephaly, cardiac anomalies, and gastrointestinal complications, genotype– phenotype correlations show that late-truncating pathogenic variants (exons 16–17) are significantly more prevalent. We highlight novel associations, including an increased risk of gastrointestinal obstruction. Conclusion Our data expand the genotypic and phenotypic spectrum for individuals with genetic pathogenic variants in KAT6A and we outline appropriate clinical management.

GJA8 encodes connexin 50 (Cx50), a transmembrane protein involved in the formation of lens gap junctions. GJA8 mutations have been linked to early onset cataracts in humans and animal models. In mice, missense mutations and homozygous Gja8 deletions lead to smaller lenses and microphthalmia in addition to cataract, suggesting that Gja8 may play a role in both lens development and ocular growth. Following screening of GJA8 in a cohort of 426 individuals with severe congenital eye anomalies, primarily anophthalmia, microphthalmia and coloboma, we identified four known [p.(Thr39Arg), p.(Trp45Leu), p.(Asp51Asn), and p.(Gly94Arg)] and two novel [p.(Phe70Leu) and p.(Val97Gly)] likely pathogenic variants in seven families. Five of these co-segregated with cataracts and microphthalmia, whereas the variant p.(Gly94Arg) was identified in an individual with congenital aphakia, sclerocornea, microphthalmia and coloboma. Four missense variants of unknown or unlikely clinical significance were also identified. Furthermore, the screening of GJA8 structural variants in a subgroup of 188 individuals identified heterozygous 1q21 microdeletions in five families with coloboma and other ocular and/or extraocular findings. However, the exact genotype–phenotype correlation of these structural variants remains to be established. Our data expand the spectrum of GJA8 variants and associated phenotypes, confirming the importance of this gene in early eye development.

Peutz–Jeghers syndrome (PJS) is an autosomal dominant cancer predisposition syndrome characterised by gastrointestinal polyposis and mucocutaneous pigmentation. Mutations in STK11 , a serine–threonine protein kinase, have been associated with PJS in up to 100 % of published series. The hypothesis that a further genetic locus for PJS exists is controversial. No mutations in any other genes have been described in association with PJS. To date, no instances of somatic mosaicism for STK11 have been described. DNA extracted from peripheral lymphocytes and buccal cells was screened by sequence analysis for mutations in STK11 . Dosage analysis was undertaken by multiplex ligation-dependent probe amplification (MLPA). Four patients have been shown to have mosaicism in STK11 : two had mosaic deletions of specific exons (2–3 and 3–10) of the STK11 gene; one had a mosaic nonsense mutation in exon 5; and one had a mosaic frameshift mutation in exon 8. This report details the first four reported cases of somatic mosaicism for STK11 associated with PJS. This shows that techniques in addition to direct sequencing such as MLPA must be used to assess for large scale genomic deletions in patients meeting clinical diagnostic criteria for PJS. This also adds further weight to the hypothesis of a single genetic locus for PJS.

The etiological spectrum of ultra-rare developmental disorders remains to be fully defined. Chromatin regulatory mechanisms maintain cellular identity and function, where misregulation may lead to developmental defects. Here, we report pathogenic variations in MSL3, which encodes a member of the chromatin-associated male-specific lethal (MSL) complex responsible for bulk histone H4 lysine 16 acetylation (H4K16ac) in flies and mammals. These variants cause an X-linked syndrome affecting both sexes. Clinical features of the syndrome include global developmental delay, progressive gait disturbance, and recognizable facial dysmorphism. MSL3 mutations affect MSL complex assembly and activity, accompanied by a pronounced loss of H4K16ac levels in vivo. Patient-derived cells display global transcriptome alterations of pathways involved in morphogenesis and cell migration. Finally, we use histone deacetylase inhibitors to rebalance acetylation levels, alleviating some of the molecular and cellular phenotypes of patient cells. Taken together, we characterize a syndrome that allowed us to decipher the developmental importance of MSL3 in humans. De novo mutations in MSL3 cause an X-linked syndrome affecting both males and females. MSL3 mutations reduce H4K16ac levels and lead to misregulation of cellular pathways involved in morphogenesis, cellular shape, and cell migration.

BackgroundHCM is a disease characterised by otherwise unexplained hypertrophy of the myocardium, often as a result of a gene mutation. Phenotypic expression is estimated at 1 in 500 and genetic prevalence at 1 in 200. Genetic testing is used primarily to facilitate predictive testing in family members.MethodA retrospective analysis of 174 consecutive HCM patients undergoing diagnostic genetic testing at a tertiary referral service in Liverpool, UK (January 2014 – February 2019) was performed. Univariate and multivariate analysis was performed on pre-defined clinical characteristics. Left ventricular morphology was assessed using echocardiography and cardiac MRI. Morphology was categorised into five groups: reverse curve, sigmoid, apical, concentric and focal. Standard HCM panels were performed via Oxford and Royal Brompton genetic laboratories. Class 4 and 5 variants were deemed ‘informative’.Results72/174 (41.4%) genetic tests were informative. Those with informative tests were younger, with a mean age of 48.9 (confidence interval (CI) 45.5–52.3). Those with uninformative results had a mean age of 54.6 (CI 52.1–57.1) There was a higher incidence of positive Family History (FH) for HCM or sudden cardiac death (SCD) (43.1% vs 20.6%, p=0.002) in those with informative tests. Reverse curve morphology of the septum was seen in 70.8% of informative tests.Multivariate analysis demonstrated that reverse curve morphology (Odds ratio (OR) 2.85, CI 1.45–5.57, p=0.002), FH of SCD/HCM (OR 2.18, CI 1.07–4.42, p=0.031) and younger age at time of testing (OR 0.97, CI 0.94–0.99, p=0.007) were predictive of an informative test.Univariate analysis demonstrated that maximum wall width, T wave inversion on ECG and non-sustained VT on ambulatory ECG were not predictive of an informative test (n=125).An informative test was seen in 75.0% (12/16) of patients with all 3 predictors of age<50, FH HCM/SCD and reverse curve morphology. If 2 of 3 factors were seen, the chance of an informative test fell to 63.8% (30/47), 1 factor=29.9% (23/77) and 0 factors=20.6% (7/34). Patients with reverse curve morphology had informative genetic tests in 54.3% of cases (51/94) regardless of age at presentation.Those with an informative test were more likely to have an ICD. Of the 72 informative results, 26 had an ICD implanted compared with 20/102 with uninformative results (36.1% vs 19.6%, p=0.022).Variants in MYBPC3 were the most frequent accounting for 39 of the 72 (54.2%). MYH7 accounted for 17 cases (23.6%), TNNI3 for 4 (5.6%), FLNC=3 (4.2%), GLA=2 (2.8%), ACTC1=2 (2.8%), TNNT2=2 (2.8%), MYL2=1 (1.4%), MYL3=1 (1.4%) and TPM1=1 (1.4%).ConclusionReverse curve morphology of the septum (OR 2.85, CI 1.45–5.57), FH of SCD or HCM (OR 2.18, CI 1.07–4.42) and younger age at testing (OR 0.97, CI 0.94–0.99), are predictors of informative genetic testing in HCM, especially when two or more of these variables occur simultaneously (Table 1).Abstract 134 Figure 1Abstract 134 Figure 2Abstract 134 Table 1Multivariate regression analysis using predefined clinical characteristicsAbstract 134 Table 2The likelihood of an informative test using a predictive modelFactors: Age <50, FH SCD/HCM, reverse curve septal morphologyConflict of InterestNone

An amendment to this paper has been published and can be accessed via a link at the top of the paper.An amendment to this paper has been published and can be accessed via a link at the top of the paper.