Correction: KAT6A Syndrome: genotype-phenotype correlation in 76 patients with pathogenic KAT6A variants.

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

New GJA8 variants and phenotypes highlight its critical role in a broad spectrum of eye anomalies.

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.

KAT6A Syndrome: genotype-phenotype correlation in 76 patients with pathogenic KAT6A variants.

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.

Will the real Moebius syndrome please stand up? A systematic review of the literature and statistical cluster analysis of clinical features.

Moebius syndrome is a highly variable syndrome with abducens and facial nerve palsy as core features. Strict diagnostic criteria do not exist and the inconsistency of the associated features makes determination difficult. To determine what features are associated with Moebius syndrome we performed a systematic literature review resulting in a composite case series of 449 individuals labeled with Moebius syndrome. We applied minimum criteria (facial and abducens palsy) to determine the prevalence of associated clinical features in this series. Additionally, we performed statistical cluster analysis to determine which features tended to occur together. Our study comprises the largest series of patients with Moebius syndrome and the first to apply statistical methodology to elucidate clinical relationships. We present evidence for two groups within the Moebius diagnosis. Type 1: exhibiting micrognathia, limb anomalies and feeding/swallowing difficulty that tend to occur together. Type 2: phenotypically diverse but more associated with radiologically detectable neurologic abnormalities and developmental delay.

Heterozygous mutations affecting the protein kinase domain of CDK13 cause a syndromic form of developmental delay and intellectual disability.

INTRODUCTION: Recent 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. METHODS: Patients were investigated by exome sequencing, having presented with developmental delay and additional features suggestive of a syndromic cause. RESULTS: Our 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. CONCLUSIONS: These 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.

Diagnosis of lethal or prenatal-onset autosomal recessive disorders by parental exome sequencing.

OBJECTIVE: Rare genetic disorders resulting in prenatal or neonatal death are genetically heterogeneous, but testing is often limited by the availability of fetal DNA, leaving couples without a potential prenatal test for future pregnancies. We describe our novel strategy of exome sequencing parental DNA samples to diagnose recessive monogenic disorders in an audit of the first 50 couples referred. METHOD: Exome sequencing was carried out in a consecutive series of 50 couples who had 1 or more pregnancies affected with a lethal or prenatal-onset disorder. In all cases, there was insufficient DNA for exome sequencing of the affected fetus. Heterozygous rare variants (MAF < 0.001) in the same gene in both parents were selected for analysis. Likely, disease-causing variants were tested in fetal DNA to confirm co-segregation. RESULTS: Parental exome analysis identified heterozygous pathogenic (or likely pathogenic) variants in 24 different genes in 26/50 couples (52%). Where 2 or more fetuses were affected, a genetic diagnosis was obtained in 18/29 cases (62%). In most cases, the clinical features were typical of the disorder, but in others, they result from a hypomorphic variant or represent the most severe form of a variable phenotypic spectrum. CONCLUSION: We conclude that exome sequencing of parental samples is a powerful strategy with high clinical utility for the genetic diagnosis of lethal or prenatal-onset recessive disorders. © 2017 The Authors Prenatal Diagnosis published by John Wiley & Sons Ltd.

Current use of chromosomal microarray by Australian paediatricians and implications for the implementation of next generation sequencing.

AIM: Chromosomal microarray (CMA) is an important diagnostic test for children with multiple congenital anomalies or certain developmental behavioural problems suggestive of an underlying genetic diagnosis. However, there are medical and ethical complexities to its use and few Australian policies to guide practice. We aimed to describe the current practice of Australian paediatricians in relation to CMA testing. We hypothesised that there are knowledge gaps in their use of CMA. METHODS: Online survey completed between September 2015 and January 2016 by paediatricians in secondary care settings. Participants were members of the Australian Paediatric Research Network. One hundred and sixty five (43%) of 383 active members responded. Our main outcome measures comprised: (i) the indications for which paediatricians request CMA; (ii) their approach to consent; (iii) their interpretation of results; and (iv) their understanding of the impact on patient management. RESULTS: A significant proportion of paediatricians (21-52%) did not regularly use CMA for conditions with established evidence of diagnostic yield. Paediatricians under-estimated the potential for CMA findings to alter patient management. There was wide variability in paediatricians' approach to consent, and low use of consent forms and fact sheets. Paediatricians reported difficulties interpreting CMA results, with high rates of referral to clinical genetics services. CONCLUSIONS: The reported practice of Australian paediatricians is not consistent with international standards on CMA. Australian practice could be improved by a standardised approach to ordering CMA, consenting patients and interpreting results. We provide resources for CMA ordering and make recommendations about preparation for next generation sequencing.

Multidisciplinary Care for Moebius Syndrome and Related Disorders: Building a Management Protocol.

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.

Screening for the vulnerable aorta: targeting high-risk groups in the population.

Thoracic aortic aneurysms are often asymptomatic until patients present with a life-threatening acute aortic syndrome. The vulnerability of an aorta to an acute aortic syndrome is determined by cross-sectional diameter and underlying aetiological factors, such as genotype or acquired disease. Screening the general population for thoracic aneurysms presents multiple resource issues including the availability of imaging modalities. Targeted screening of high-risk groups provides the only currently pragmatic solution. Opportunistic imaging through lung cancer screening programmes could pick up a proportion. Until we have a comprehensive screening programme it is incumbent on all healthcare professionals to have a low threshold for considering acute aortic pathologies when reviewing patients presenting with chest pain.