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Missense and truncating variants in the X-chromosome-linked CLCN4 gene, resulting in reduced or complete loss-of-function (LOF) of the encoded chloride/proton exchanger ClC-4, were recently demonstrated to cause a neurocognitive phenotype in both males and females. Through international clinical matchmaking and interrogation of public variant databases we assembled a database of 90 rare CLCN4 missense variants in 90 families: 41 unique and 18 recurrent variants in 49 families. For 43 families, including 22 males and 33 females, we collated detailed clinical and segregation data. To confirm causality of variants and to obtain insight into disease mechanisms, we investigated the effect on electrophysiological properties of 59 of the variants in Xenopus oocytes using extended voltage and pH ranges. Detailed analyses revealed new pathophysiological mechanisms: 25% (15/59) of variants demonstrated LOF, characterized by a “shift” of the voltage-dependent activation to more positive voltages, and nine variants resulted in a toxic gain-of-function, associated with a disrupted gate allowing inward transport at negative voltages. Functional results were not always in line with in silico pathogenicity scores, highlighting the complexity of pathogenicity assessment for accurate genetic counselling. The complex neurocognitive and psychiatric manifestations of this condition, and hitherto under-recognized impacts on growth, gastrointestinal function, and motor control are discussed. Including published cases, we summarize features in 122 individuals from 67 families with CLCN4-related neurodevelopmental condition and suggest future research directions with the aim of improving the integrated care for individuals with this diagnosis.

Background: The UK 100,000 Genomes Project was a transformational research project which facilitated whole genome sequencing (WGS) diagnostics for rare diseases. We evaluated experiences of introducing WGS in Northern Ireland, providing recommendations for future projects. Methods: This formative evaluation included (1) an appraisal of the logistics of implementing and delivering WGS, (2) a survey of participant self-reported views and experiences, (3) semi-structured interviews with healthcare staff as key informants who were involved in the delivery of WGS and (4) a workshop discussion about interprofessional collaboration with respect to molecular diagnostics. Results: We engaged with >400 participants, with detailed reflections obtained from 74 participants including patients, caregivers, key National Health Service (NHS) informants, and researchers (patient survey n = 42; semi-structured interviews n = 19; attendees of the discussion workshop n = 13). Overarching themes included the need to improve rare disease awareness, education, and support services, as well as interprofessional collaboration being central to an effective, mainstreamed molecular diagnostic service. Conclusions: Recommendations for streamlining precision medicine for patients with rare diseases include administrative improvements (e.g., streamlining of the consent process), educational improvements (e.g., rare disease training provided from undergraduate to postgraduate education alongside genomics training for non-genetic specialists) and analytical improvements (e.g., multidisciplinary collaboration and improved computational infrastructure).

BRWD3 has been described as a cause of X-linked intellectual disability, but relatively little is known about the specific phenotype. We report the largest BRWD3 patient series to date, comprising 17 males with 12 distinct null variants and two partial gene deletions. All patients presented with intellectual disability, which was classified as moderate (65%) or mild (35%). Behavioral issues were present in 75% of patients, including aggressive behavior, attention deficit/hyperactivity and/or autistic spectrum disorders. Mean head circumference was +2.8 SD (2.8 standard deviations above the mean), and mean BMI was +2.0 SD (in the context of a mean height of +1.3 SD), indicating a predominant macrocephaly/obesity phenotype. Shared facial features included a tall chin, prognathism, broad forehead, and prominent supraorbital ridge. Additional features, reported in a minority (

PurposeLamins are the major component of nuclear lamina, maintaining structural integrity of the nucleus. Lamin A/C variants are well established to cause a spectrum of disorders ranging from myopathies to progeria, termed laminopathies. Phenotypes resulting from variants in LMNB1 and LMNB2 have been much less clearly defined.MethodsWe investigated exome and genome sequencing from the Deciphering Developmental Disorders Study and the 100,000 Genomes Project to identify novel microcephaly genes.ResultsStarting from a cohort of patients with extreme microcephaly, 13 individuals with heterozygous variants in the two human B-type lamins were identified. Recurrent variants were established to be de novo in nine cases and shown to affect highly conserved residues within the lamin ɑ-helical rod domain, likely disrupting interactions required for higher-order assembly of lamin filaments.ConclusionWe identify dominant pathogenic variants in LMNB1 and LMNB2 as a genetic cause of primary microcephaly, implicating a major structural component of the nuclear envelope in its etiology and defining a new form of laminopathy. The distinct nature of this lamin B–associated phenotype highlights the strikingly different developmental requirements for lamin paralogs and suggests a novel mechanism for primary microcephaly warranting future investigation.

ObjectiveTo identify the phenotypic, neuroimaging, and genotype-phenotype expression of MYORG mutations.MethodsUsing next-generation sequencing, we screened 86 patients with primary familial brain calcification (PFBC) from 60 families with autosomal recessive or absent family history that were negative for mutations in SLC20A2, PDGFRB, PDGBB, and XPR1. In-depth phenotyping and neuroimaging investigations were performed in all cases reported here.ResultsWe identified 12 distinct deleterious MYORG variants in 7 of the 60 families with PFBC. Overall, biallelic MYORG mutations accounted for 11.6% of PFBC families in our cohort. A heterogeneous phenotypic expression was identified within and between families with a median age at onset of 56.4 years, a variable combination of parkinsonism, cerebellar signs, and cognitive decline. Psychiatric disturbances were not a prominent feature. Cognitive assessment showed impaired cognitive function in 62.5% of cases. Parkinsonism associated with vertical nuclear gaze palsy was the initial clinical presentation in 1/3 of cases and was associated with central pontine calcifications. Cerebral cortical atrophy was present in 37% of cases.ConclusionsThis large, multicentric study shows that biallelic MYORG mutations represent a significant proportion of autosomal recessive PFBC. We recommend screening MYORG mutations in all patients with primary brain calcifications and autosomal recessive or negative family history, especially when presenting clinically as atypical parkinsonism and with pontine calcification on brain CT.

An 8-month-old boy presented with a week’s history of left lower limb swelling. He was apyrexic, well and developmentally age appropriate. He was born at 35+5 via by C-section for breech presentation, weighing 3.47 kg (97th centile). His left calf measured 21.5 cm and the right calf 19.5 cm. The overlying skin showed mild eczema. There was no circulatory compromise of the left leg, and he was systemically well. X-rays of the left tibia and fibula were normal. He received oral antibiotics for presumed cellulitis. A follow-up showed some improvement (figure 1). A subsequent Doppler ultrasound of the left leg was normal. He continued to show size variation of the calf (figure 2). A pit on the helix of left ear and a faded haemangioma over left eyelid were noted. Blood investigations including full blood count, C reactive protein, electrolytes, muscle enzymes (CK), liver, thyroid, bone profile, alpha feto protein and insulin-like growth factor 1 were normal. Abdominal scan was normal. Questions What is the most likely diagnosis? Cellulitis Perlman syndrome Sotos syndrome Beckwith-Wiedemann syndrome (BWS) Simpson-Golabi-Behmel syndrome Deep venous thrombosis (DVT) What should we do next? How would you manage the condition? What are the complications associated with this condition? Answers can be found on page 2.

Spinocerebellar ataxia type 5 (SCA-5) is a predominantly slowly progressive adult onset ataxia. We describe a child with a presentation of ataxic cerebral palsy (CP) and developmental delay at 6 months of age. Genetic testing confirmed a c.812C>T p.(Thr271Ile) mutation within the SPTBN2 gene. Seven previous cases of infantile onset SCA-5 are reported in the literature, four of which had a CP presentation. Early onset of SCA-5 presents with ataxic CP and is a rare cause of cerebral palsy.

Otodental syndrome is a hereditary disorder comprising globodontia and sensorineural hearing loss. Globodontia is characterized by distinctively bulbous, enlarged crowns of molar and primary canine teeth. Anomalies including taurodontism and hypodontia also occur. We report on the dental treatment and multidisciplinary management of an eight-year-old girl with this rare condition. Referral to Clinical Genetics and Oral Pathology was instrumental in establishing a diagnosis of otodental syndrome for this young patient and her mother, who had similar dental defects. CPD/Clinical Relevance: To increase awareness among practitioners of this rare dental disorder and highlight the need for multidisciplinary management of such cases.

The field of aortopathy, in common with other genomic disorders, is undergoing a revolution. This is largely driven by the implementation of newer forms of genetic sequencing (massively parallel or next-generation sequencing). Advantages conferred by this technology include reduced costs, reduced sequencing time and the ability to simultaneously test multiple genes. This has a significant advantage in the identification of genes disrupted in heritable aortopathies. These advances are enabling scientists and clinicians to identify key molecular pathways; translating fundamental genetic findings into a better understanding of disease mechanisms is ultimately leading to effective treatments. In outlining contemporary knowledge of genetic biomarkers in aortopathy we seek to demonstrate that the era of genomically orientated decision-making is here.

Interstitial deletions of chromosome 3q22.3–25.1 are very rare with only five previous reports of deletions in this region [1] , [2] , [4] , [7] , [9] . We describe a case of a female infant with a de novo deletion. Dysmorphic features and congenital heart disease led to a clinical genetics assessment on day 1 of life. Chromosomal analysis showed an interstitial deletion with a female karyotype 46,XX,del (3)(q23q25.1)dn. Subsequent array CGH demonstrated the breakpoints as 3q22.3q25.1. This is the first documented association with a truncus arteriosus. We identify an emerging clinical phenotype of microphthalmia, microcephaly, congenital heart disease, slow feeding, skeletal abnormalities, with an abnormal facies and developmental delay. Array CGH demonstrated that the FOXL2 gene responsible for BPES was not deleted in this patient.

The titingene ( TTN ) is a major determinant of myocardial function, its importance in both familial and ‘idiopathic’ Dilated Cardiomyopathy (DCM) has recently been ascertained. In some instances a second genetic mutation or a physiological perturbation (e.g. pregnancy) may reveal otherwise latent TTN mutation effects. We hypothesise that patients with pronounced LV dysfunction following MI, when controlling for infarct parameters and coronary anatomy, may have a high burden of TTN truncating variants (TTNtvs). We studied a large cohort of post-MI patients prospectively recruited at the Royal Brompton and Harefield NHS Foundation Trust. Gadolinium-enhanced Cardiac Magnetic Resonance was used to characterise cardiac dimensions, function and tissue properties. The size and thickness of MI, wall motion and number of hibernating segments were quantified by two experts blinded to genotype using a standard 17-segment model. Targeted re-sequencing of TTN and other key DCM genes was performed. Genetic variation in DCM genes in 530ethnically matchedhealthy volunteers along with public repositories was used for variant annotation and comparison. Our initial analyses show that out of the 336 post-MI patients, nine (2.7%) had a TTNtv. As hypothesised, TTNtv were significantly enriched in patients with LV ejection fraction (LVEF) TTNtv , in post-MI systolic dysfunction. Based on these findings it will be important to explore if genetic stratification of the post-MI patient can inform medical or revascularisation strategies.

We present a case of classical Menkes disease (MD) due to a novel "silent" substitution in the ATP7A gene; c.2781G>A (p.K927K). The affected nucleotide is the last nucleotide in exon 13, and affects mRNA splicing. Transcripts missing exon 13; and transcripts missing exons 11, 12 and 13 in addition to a very small amount of normal spliced ATP7A transcripts were expressed. This is the first report of a synonymous ATP7A substitution being responsible for MD.

Histiocytoid cardiomyopathy (CM) is a rare, distinctive form of cardiomyopathy, characterised by malignant arrhythmias and associated sudden death. ~90% of cases present in females de novo nonsense mutation in NDUFB11 (c.262C>T; p. Arg88*) , located on the X chromosome and encoding a component of the mitochondrial respiratory chain (MRC). Mutations in NDUFB11, including one identical to the one we describe here, have been reported to cause microphthalmia and linear skin defects syndrome (MLS). During the course of our studies, additional mutations in NDUFB11 were associated with Histiocytoid CM by another group. Four of the affected individuals in our study did not carry variants in NDUFB11. Heterozygous mutations in HCCS (which encodes an important mitochondrially-targeted protein) and COX7B ( which, like NDUFB11, encodes a protein of the MRC) have also previously been identified in MLS syndrome including a case with features of both MLS syndrome and Histiocytoid CM. However, a systematic review of WES data from previously published cases, alongside the four additional cases presented here, did not identify any further mutations in these genes in Histiocytoid CM. We conclude thattruncating variants in NDUFB11 link the distinct phenotypes of Histiocytoid CM and MLS syndrome. Screening for malignant arrhythmias and cardiomyopathy would be appropriate in individuals with MLS syndrome. Additional nuclear encoded mitochondrial or mitochondrial DNA genes are good candidates for further causes of both Histiocytoid CM and MLS syndrome.