Recurrent de novo missense variants across multiple histone H4 genes underlie a neurodevelopmental syndrome.

Chromatin is essentially an array of nucleosomes, each of which consists of the DNA double-stranded fiber wrapped around a histone octamer. This organization supports cellular processes such as DNA replication, DNA transcription, and DNA repair in all eukaryotes. Human histone H4 is encoded by fourteen canonical histone H4 genes, all differing at the nucleotide level but encoding an invariant protein. Here, we present a cohort of 29 subjects with de novo missense variants in six H4 genes (H4C3, H4C4, H4C5, H4C6, H4C9, and H4C11) identified by whole-exome sequencing and matchmaking. All individuals present with neurodevelopmental features of intellectual disability and motor and/or gross developmental delay, while non-neurological features are more variable. Ten amino acids are affected, six recurrently, and are all located within the H4 core or C-terminal tail. These variants cluster to specific regions of the core H4 globular domain, where protein-protein interactions occur with either other histone subunits or histone chaperones. Functional consequences of the identified variants were evaluated in zebrafish embryos, which displayed abnormal general development, defective head organs, and reduced body axis length, providing compelling evidence for the causality of the reported disorder(s). While multiple developmental syndromes have been linked to chromatin-associated factors, missense-bearing histone variants (e.g., H3 oncohistones) are only recently emerging as a major cause of pathogenicity. Our findings establish a broader involvement of H4 variants in developmental syndromes.

Clinical phenotype of FOXP1 syndrome: parent-reported medical signs and symptoms in 40 individuals.

BACKGROUND: The first studies on patients with forkhead-box protein P1 (FOXP1) syndrome reported associated global neurodevelopmental delay, autism symptomatology, dysmorphic features and cardiac and urogenital malformations. The aim of this study was to assess the prevalence of congenital abnormalities in an unbiased cohort of patients with FOXP1 syndrome and to document rare complications. METHODS: Patients with FOXP1 syndrome were included, mostly diagnosed via whole-exome sequencing for neurodevelopmental delay. A parent-report questionnaire was used to assess medical signs and symptoms, including questions about features rated as most burdensome by patients and their family. RESULTS: Forty individuals were included, 20 females and 20 males. The mean age at assessment was 13.2 years (median 8.5 years; range 2-54 years; ≥18 years n = 7). Seven adults were included. All patients had developmental problems, including cognitive, communication, social-emotional and motor delays. The most prevalent medical signs and symptoms include delayed bladder control, sleeping problems, hypermetropia, strabismus, sacral dimple, undescended testes, abnormal muscle tone and airway infections. The most burdensome complaints for patients with FOXP1 syndrome, as perceived by parents, include intellectual disability, impaired communication, behaviour problems, lack of age-appropriate self-reliance, attention problems and anxiety. According to parents, patients have quite similar reported symptoms, although incontinence, obsessions and a complex sensory profile have a higher ranking. CONCLUSION: The results of this study may be used to further guide medical management and identify patient priorities for future research targeted on those features of FOXP1 syndrome that most impair quality of life of patients and their families.

The heterogeneous cancer phenotype of individuals with biallelic germline pathogenic variants in CHEK2.

PURPOSE: Females with biallelic CHEK2 germline pathogenic variants (gPVs) more often develop multiple breast cancers than individuals with monoallelic CHEK2 gPVs. This study is aimed at expanding the knowledge on the occurrence of other malignancies. METHODS: Exome sequencing of individuals who developed multiple primary malignancies identified 3 individuals with the CHEK2 (NM_007194.4) c.1100del p.(Thr367MetfsTer15) loss-of-function gPV in a biallelic state. We collected the phenotypes of an additional cohort of individuals with CHEK2 biallelic gPVs (n = 291). RESULTS: In total, 157 individuals (53.4%; 157/294 individuals) developed ≥1 (pre)malignancy. The most common (pre)malignancies next to breast cancer were colorectal- (n = 19), thyroid- (n = 19), and prostate (pre)malignancies (n = 12). Females with biallelic CHEK2 loss-of-function gPVs more frequently developed ≥2 (pre)malignancies and at an earlier age compared with females biallelic for the CHEK2 c.470T>C p.(Ile157Thr) missense variant. Furthermore, 26 males (31%; 26/84 males) with CHEK2 biallelic gPVs developed ≥1 (pre)malignancies of 15 origins. CONCLUSION: Our study suggests that CHEK2 biallelic gPVs likely increase the susceptibility to develop multiple malignancies in various tissues, both in females and males. However, it is possible that a substantial proportion of individuals with CHEK2 biallelic gPVs is missed as diagnostic testing for CHEK2 often is limited to individuals who developed breast cancer.

Reanalysis of whole-exome sequencing (WES) data of children with neurodevelopmental disorders in a standard patient care context.

This study aims to inform future genetic reanalysis management by evaluating the yield of whole-exome sequencing (WES) reanalysis in standard patient care in the Netherlands. Single-center data of 159 patients with a neurodevelopmental disorder (NDD), in which WES analysis and reanalysis were performed between January 1, 2014, and December 31, 2021, was retrospectively collected. Patients were included if they were under the age of 18 years at initial analysis and if this initial analysis did not result in a diagnosis. Demographic, phenotypic, and genotypic characteristics of patients were collected and analyzed. The primary outcomes of our study were (i) diagnostic yield at reanalysis, (ii) reasons for detecting a new possibly causal variant at reanalysis, (iii) unsolicited findings, and (iv) factors associated with positive result of reanalysis. In addition, we conducted a questionnaire study amongst the 7 genetic department in the Netherlands creating an overview of used techniques, yield, and organization of WES reanalysis. The single-center data show that in most cases, WES reanalysis was initiated by the clinical geneticist (65%) or treating physician (30%). The mean time between initial WES analysis and reanalysis was 3.7 years. A new (likely) pathogenic variant or VUS with a clear link to the phenotype was found in 20 initially negative cases, resulting in a diagnostic yield of 12.6%. In 75% of these patients, the diagnosis had clinical consequences, as for example, a screening plan for associated signs and symptoms could be devised. Most (32%) of the (likely) causal variants identified at WES reanalysis were discovered due to a newly described gene-disease association. In addition to the 12.6% diagnostic yield based on new diagnoses, reclassification of a variant of uncertain significance found at initial analysis led to a definite diagnosis in three patients. Diagnostic yield was higher in patients with dysmorphic features compared to patients without clear dysmorphic features (yield 27% vs. 6%; p = 0.001). CONCLUSIONS: Our results show that WES reanalysis in patients with NDD in standard patient care leads to a substantial increase in genetic diagnoses. In the majority of newly diagnosed patients, the diagnosis had clinical consequences. Knowledge about the clinical impact of WES reanalysis, clinical characteristics associated with higher yield, and the yield per year after a negative WES in larger clinical cohorts is warranted to inform guidelines for genetic reanalysis. These guidelines will be of great value for pediatricians, pediatric rehabilitation specialists, and pediatric neurologists in daily care of patients with NDD. WHAT IS KNOWN: • Whole exome sequencing can cost-effectively identify a genetic cause of intellectual disability in about 30-40% of patients. • WES reanalysis in a research setting can lead to a definitive diagnosis in 10-20% of previously exome negative cases. WHAT IS NEW: • WES reanalysis in standard patient care resulted in a diagnostic yield of 13% in previously exome negative children with NDD. • The presence of dysmorphic features is associated with an increased diagnostic yield of WES reanalysis.

Perceive, Recall, Plan and Perform (PRPP)-Assessment Based on Parent-Provided Videos of Children with Mitochondrial Disorder: Action Design Research on Implementation Challenges.

AIMS: Performing the Perceive, Recall, Plan and Perform (PRPP)-Assessment, using video material of everyday life, seems sensible to lower the patient burden, enhance ecological validity, and provide care at a distance. However, receipt of adequate video material is not self-evident and assessing videos can be challenging. Therefore, this study aims to optimize the process of gaining video material and to optimize the PRPP-Assessment based on parent-provided videos. METHODS: An action design research method was used, focusing on implementation of the PRPP-Assessment based on parent-provided videos within the care of children with a mitochondrial disorder or similar symptoms. RESULTS: Five cycles were conducted. To receive input, the cycles used videos of nine children performing activities, written feedback, and semi-structured interviews and focus groups comprising parents (n = 13), a teacher (n = 1), occupational therapists (n = 16), and other professionals (n = 2) . This led to successful implementation of the PRPP-Assessment. General lessons were learned on (1) instructing parents; (2) handling video material; (3) PRPP-Assessment based on parent-provided videos; and (4) PRPP-Assessment of children (with limited functional abilities). CONCLUSIONS: Lessons learned should be implemented in practice and are incorporated into a manual to guide the implementation of video-based observations with PRPP-Assessment in practice.

Tailored interviewing to uncover the perspectives of children with multiple disabilities on daily activities: A qualitative analyses of interview methods and interviewer skills.

INTRODUCTION: Uncovering the perspective of children with multiple disabilities is important in health care to enable person-centred health care. For occupational therapists, uncovering the child perspective on meaningful activities is necessary to set appropriate goals for treatment. It is not always evident that children with multiple disabilities can express themselves in an interview. The interviewer should adapt his communication to the child. In literature, alternative communication is widely studied, but a clear algorithm for deciding what to use to successfully gain insight into the child perspective is missing. This study aims to identify helpful interview techniques and interviewer skills and how they can be used to effectively uncover the perspective of children. METHODS: Videos of nine interviews with children with a mitochondrial disorder, conducted by an occupational therapist, were analysed by five researchers. The interviews were analysed to see how well the interviewee had obtained the child's perspectives followed by observation of communicative abilities of the child and the types of questions the interviewer asked. A qualitative directed content analysis of the semi-structured interviews followed. FINDINGS: An interview pattern was observed in the children's communication leading to six successful interviews. Children communicated verbally on four different levels and also used non-verbal communication. The interviewer used five types of questions, which varied between and within the children. The content analysis resulted in two themes: parental influences and interviewer skills. CONCLUSION: Results show the importance of matching the type of questions to the verbal communication level of the child and revealed several interviewer skills and techniques. An overview to guide tailor-made interviewing is presented. The interviewer has a major role in successful interviewing and thus in enabling the inclusion of the child perspective in research and care.

Using PRPP-Assessment for measuring change in everyday activities by home-based videos: An exploratory case series study in children with multiple disabilities.

BACKGROUND: Currently, paediatric health care aims to use a child-centred tailor-made approach. In order to design tailored occupational therapy, the implementation of personalised occupation-based measurements that guide and evaluate goal setting and are responsive to change is necessary. PURPOSE: Primarily, this study explored the potential of the Perceive, Recall, Plan, and Perform (PRPP) assessment to measure the change in the performance of children with multiple disabilities. As a secondary evaluation, the feasibility of the PRPP-Intervention in a home-based program to enable activities was described. The overall aim is to show the potential of the PRPP-Assessment as an outcome measure to use as a base for designing tailor-made person-centred care. METHODS: An exploratory longitudinal multiple case series mixed-methods design was used. The PRPP-Assessment, scored by multiple raters, was conducted based on parent-provided videos. The assessed activities were chosen by the child and/or parents. Responsiveness was evaluated by hypotheses formulated a priori and by comparing measured change with change on concurrent measures: Goal Attainment Scaling (GAS) and Canadian Occupational Performance Measure (COPM). Over a 6-week period, children and their parents (or caregivers) participated in an online home-based video coaching program where parents were coached in the implementation of the training, based on the PRPP-Intervention, by paediatric occupational therapists on a weekly basis. The feasibility of the intervention was explored using semi-structured interviews with children, parents, and the treating occupational therapists and was analysed by directed content analysis. RESULTS: Three out of 17 eligible children agreed to participate and completed post-intervention measurement, of which two completed the intervention. Quantitative results showed that eight out of nine activities improved on the PRPP-Assessment and the COPM, and nine improved on the GAS. In total, 13 out of 15 hypotheses for responsiveness were accepted. Participants experienced the intervention as successful and acceptable. Facilitators and concerns over demand, implementation, practicality, integration, and adaptation were shared. CONCLUSION: The PRPP-Assessment showed the potential to measure change in a heterogeneous group of children. The results indicated a positive tendency for the intervention and also provide directions for further development.

Hearing loss, cleft palate, and congenital hip dysplasia in female carriers of an intragenic deletion of AMMECR1.

Previously, mutations in the AMMECR1 gene have been described in six males with developmental delay, sensorineural hearing loss (SNHL) and/or congenital abnormalities, including fetal nuchal edema, fetal pericardial effusion, talipes, congenital hip dysplasia, elliptocytosis and cleft palate. In this report, we present three female relatives of a male fetus with an intragenic deletion in this X-linked gene. All three women reported hearing loss and one was born with a soft cleft palate and hip dysplasia. The audiograms showed mild to moderate SNHL with a variable pattern of the affected frequencies. Immunohistochemical analysis of fetal cochlea was performed confirming the expression of AMMECR1 in the human inner ear. Since hearing loss, cleft palate and congenital hip dysplasia were reported before in male AMMECR1 point mutation carriers and AMMECR1 is expressed in fetal inner ear, we suggest that female carriers may display a partial phenotype in this X-linked condition.

Sacral abnormalities including caudal appendage, skeletal dysplasia, and prenatal cardiomyopathy associated with a pathogenic TAB2 variant in a 3-generation family.

Haplo-insufficiency of the TGFß-activated kinase 1 binding protein 2 (TAB2) gene is associated with short stature, facial dysmorphisms, connective tissue abnormalities, hearing loss, and cardiac disease. Skeletal dysplasia and sacral dimples are also found in a minority of patients. Here, we describe a 3-generation family with caudal appendage, other sacral anomalies, and skeletal abnormalities including hypoplasia of the iliac wings and scapulae, fusion of the carpal bones and stenosis of the spinal canal, as well as a remarkable course of prenatally-detected cardiomyopathy with characteristics changing over time. Genetic analysis showed a heterozygous nonsense variant in the TAB2 gene.

Six-year prospective follow-up study in 151 carriers of the mitochondrial DNA 3243 A>G variant.

BACKGROUND: The mitochondrial DNA (mDNA) 3243A>G variant is the most common pathogenic variant of the mDNA. To interpret results of clinical trials in mitochondrial disease, it is important to have a clear understanding of the natural course of disease. To obtain more insight into the disease burden and the progression of disease in carriers of the mDNA 3243 A>G variant, we followed a cohort of 151 carriers from 61 families prospectively for up to 6 years. METHODS: The disease severity was scored using the Newcastle Mitochondrial Disease Adult Scale (NMDAS), including SF-36 quality of life (QoL) scores. Heteroplasmy levels were measured in urinary epithelial cells (UEC), leucocytes and saliva. The progression of the disease was studied using linear mixed model analysis. RESULTS: One hundred twenty-four carriers (out of 151) were symptomatic. Four clinical groups were identified: 1) classical mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes syndrome (n=7), 2) maternally inherited diabetes deafness syndrome (n=60), 3) 'other' (n=57) and 4) dormant carriers (n=27). A yearly increase of NMDAS score of 0.47 point was measured in the total group. Heteroplasmy levels in both leucocytes and UEC were only weakly correlated with disease severity. Physical QoL declined with age. The most important determinants of QoL decline were hearing loss, speech problems, exercise intolerance, gait instability, psychiatric problems and gastrointestinal involvement. CONCLUSION: The mDNA 3243 A>G variant causes a slowly progressive disease, with a yearly increase of NMDAS score of ~0.5 point overall with the clinical phenotype being the only determinant of disease progression.

Episignature Mapping of TRIP12 Provides Functional Insight into Clark-Baraitser Syndrome.

Clark-Baraitser syndrome is a rare autosomal dominant intellectual disability syndrome caused by pathogenic variants in the TRIP12 (Thyroid Hormone Receptor Interactor 12) gene. TRIP12 encodes an E3 ligase in the ubiquitin pathway. The ubiquitin pathway includes activating E1, conjugating E2 and ligating E3 enzymes which regulate the breakdown and sorting of proteins. This enzymatic pathway is crucial for physiological processes. A significant proportion of TRIP12 variants are currently classified as variants of unknown significance (VUS). Episignatures have been shown to represent a powerful diagnostic tool to resolve inconclusive genetic findings for Mendelian disorders and to re-classify VUSs. Here, we show the results of DNA methylation episignature analysis in 32 individuals with pathogenic, likely pathogenic and VUS variants in TRIP12. We identified a specific and sensitive DNA methylation (DNAm) episignature associated with pathogenic TRIP12 variants, establishing its utility as a clinical biomarker for Clark-Baraitser syndrome. In addition, we performed analysis of differentially methylated regions as well as functional correlation of the TRIP12 genome-wide methylation profile with the profiles of 56 additional neurodevelopmental disorders.

Intracerebral hemorrhage in a neonate with an intragenic COL4A2 duplication.

Intracerebral hemorrhage is rare in term born neonates. Besides several non-genetic risk factors, pathogenic variants in COL4A1 and COL4A2 have been described to play a role in the pathophysiology of neonatal intracerebral hemorrhage. To the best of our knowledge, no intragenic COL4A2 duplications have been reported in humans to date. We report a neonate with intracerebral hemorrhage and a de novo intragenic COL4A2 duplication. Although it is not clear yet whether this genetic factor fully explains the clinical phenotype, it may have contributed at least as a risk factor for cerebral hemorrhage. Screening for intragenic COL4A1 and COL4A2 duplications as part of collagen IV diagnostics should be considered as part of the fetal and neonatal work-up for unexplained cerebral hemorrhages and to collect more evidence of the pathogenicity of this genetic mechanism.

Phenotypic expansion of the BPTF-related neurodevelopmental disorder with dysmorphic facies and distal limb anomalies.

Neurodevelopmental disorder with dysmorphic facies and distal limb anomalies (NEDDFL), defined primarily by developmental delay/intellectual disability, speech delay, postnatal microcephaly, and dysmorphic features, is a syndrome resulting from heterozygous variants in the dosage-sensitive bromodomain PHD finger chromatin remodeler transcription factor BPTF gene. To date, only 11 individuals with NEDDFL due to de novo BPTF variants have been described. To expand the NEDDFL phenotypic spectrum, we describe the clinical features in 25 novel individuals with 20 distinct, clinically relevant variants in BPTF, including four individuals with inherited changes in BPTF. In addition to the previously described features, individuals in this cohort exhibited mild brain abnormalities, seizures, scoliosis, and a variety of ophthalmologic complications. These results further support the broad and multi-faceted complications due to haploinsufficiency of BPTF.

Natural history, outcome measures and trial readiness in LAMA2-related muscular dystrophy and SELENON-related myopathy in children and adults: protocol of the LAST STRONG study.

BACKGROUND: SELENON (SEPN1)-related myopathy (SELENON-RM) is a rare congenital myopathy characterized by slowly progressive proximal muscle weakness, early onset spine rigidity and respiratory insufficiency. A muscular dystrophy caused by mutations in the LAMA2 gene (LAMA2-related muscular dystrophy, LAMA2-MD) has a similar clinical phenotype, with either a severe, early-onset due to complete Laminin subunit α2 deficiency (merosin-deficient congenital muscular dystrophy type 1A (MDC1A)), or a mild, childhood- or adult-onset due to partial Laminin subunit α2 deficiency. For both muscle diseases, no curative treatment options exist, yet promising preclinical studies are ongoing. Currently, there is a paucity on natural history data and appropriate clinical and functional outcome measures are needed to reach trial readiness. METHODS: LAST STRONG is a natural history study in Dutch-speaking patients of all ages diagnosed with SELENON-RM or LAMA2-MD, starting August 2020. Patients have four visits at our hospital over a period of 1.5 year. At all visits, they undergo standardized neurological examination, hand-held dynamometry (age ≥ 5 years), functional measurements, questionnaires (patient report and/or parent proxy; age ≥ 2 years), muscle ultrasound including diaphragm, pulmonary function tests (spirometry, maximal inspiratory and expiratory pressure, sniff nasal inspiratory pressure; age ≥ 5 years), and accelerometry for 8 days (age ≥ 2 years); at visit one and three, they undergo cardiac evaluation (electrocardiogram, echocardiography; age ≥ 2 years), spine X-ray (age ≥ 2 years), dual-energy X-ray absorptiometry (DEXA-)scan (age ≥ 2 years) and full body magnetic resonance imaging (MRI) (age ≥ 10 years). All examinations are adapted to the patient's age and functional abilities. Correlation between key parameters within and between subsequent visits will be assessed. DISCUSSION: Our study will describe the natural history of patients diagnosed with SELENON-RM or LAMA2-MD, enabling us to select relevant clinical and functional outcome measures for reaching clinical trial-readiness. Moreover, our detailed description (deep phenotyping) of the clinical features will optimize clinical management and will establish a well-characterized baseline cohort for prospective follow-up. CONCLUSION: Our natural history study is an essential step for reaching trial readiness in SELENON-RM and LAMA2-MD. TRIAL REGISTRATION: This study has been approved by medical ethical reviewing committee Region Arnhem-Nijmegen (NL64269.091.17, 2017-3911) and is registered at ClinicalTrial.gov ( NCT04478981 ).

Quantification of gait in children with mitochondrial disease.

Mitochondrial disorders are multisystem conditions that can potentially affect gait in many ways. The aim of this study was to select the optimal protocol to quantify the spatiotemporal parameters of gait in ambulatory children with mitochondrial disorders based on feasibility, test-retest reliability, and the difference between patients and controls. Gait at self-selected pace was quantified in ambulatory children with a genetically confirmed primary mitochondrial disease using the GAITRite electronic walkway. Three protocols were tested: pre-exercise, post-exercise (after a 3-min walking test), and recovery. In 14 ambulatory patients, we showed good to perfect reliability for velocity, cadence, step length, step time, step time variability, and step width in the recovery condition. The difference between patients and 70 individually age- and gender matched healthy controls only became apparent in the post-exercise protocol. In conclusion, measuring spatiotemporal parameters of gait using the GAITRite in ambulatory children with mitochondrial disease is feasible and reliable for most of the parameters measured. When using gait analysis in future studies in children with mitochondrial disease, we advise i) to use an exercise test prior to the gait analysis, ii) to let children practice the test before the actual data collection, and iii) not to use symmetry parameters.

Outcome measures for children with mitochondrial disease: consensus recommendations for future studies from a Delphi-based international workshop.

Although there are no effective disease-modifying therapies for mitochondrial diseases, an increasing number of trials are being conducted in this rare disease group. The use of sensitive and valid endpoints is essential to test the effectiveness of potential treatments. There is no consensus on which outcome measures to use in children with mitochondrial disease. The aims of this two-day Delphi-based workshop were to (i) define the protocol for an international, multi-centre natural history study in children with mitochondrial myopathy and (ii) to select appropriate outcome measures for a validation study in children with mitochondrial encephalopathy. We suggest two sets of outcome measures for a natural history study in children with mitochondrial myopathy and for a proposed validation study in children with mitochondrial encephalopathy.

Assisted 6-minute cycling test: An exploratory study in children.

INTRODUCTION: The 6-minute walk test (6MWT) is frequently used as an outcome measure for clinical trials in neuromuscular disease. Because this submaximal endurance test is not feasible for nonambulatory patients, the motor-assisted 6-minute cycling test (A6MCT) was developed. METHODS: Nineteen children with neuromuscular disorders and children with OXPHOS-dysfunction performed the a6MCT and the 6MWT to explore feasibility and construct validity. Test-retest reproducibility was evaluated within 3 weeks. RESULTS: The assisted 6-minute cycling test was feasible in 90% and 78% of the patients with a neuromuscular disorder and OXPHOS-dysfunction, respectively. The A6MCT for legs correlated with the 6MWT in both patient groups. The assisted 6-minute cycling showed good reproducibility for both legs and arms. CONCLUSIONS: This exploratory study indicates that the assisted 6-minute cycling test is a promising outcome measure for patients with a neuromuscular disorder and patients with OXPHOS-dysfunction. Muscle Nerve, 2015. Muscle Nerve 54: 232-238, 2016.

International Paediatric Mitochondrial Disease Scale.

OBJECTIVE: There is an urgent need for reliable and universally applicable outcome measures for children with mitochondrial diseases. In this study, we aimed to adapt the currently available Newcastle Paediatric Mitochondrial Disease Scale (NPMDS) to the International Paediatric Mitochondrial Disease Scale (IPMDS) during a Delphi-based process with input from international collaborators, patients and caretakers, as well as a pilot reliability study in eight patients. Subsequently, we aimed to test the feasibility, construct validity and reliability of the IPMDS in a multicentre study. METHODS: A clinically, biochemically and genetically heterogeneous group of 17 patients (age 1.6-16 years) from five different expert centres from four different continents were evaluated in this study. RESULTS: The feasibility of the IPMDS was good, as indicated by a low number of missing items (4 %) and the positive evaluation of patients, parents and users. Principal component analysis of our small sample identified three factors, which explained 57.9 % of the variance. Good construct validity was found using hypothesis testing. The overall interrater reliability was good [median intraclass correlation coefficient for agreement between raters (ICCagreement) 0.85; range 0.23-0.99). CONCLUSION: In conclusion, we suggest using the IPMDS for assessing natural history in children with mitochondrial diseases. These data should be used to further explore construct validity of the IPMDS and to set age limits. In parallel, responsiveness and the minimal clinically important difference should be studied to facilitate sample size calculations in future clinical trials.

The genomic landscape of breast and non-breast cancers from individuals with germline CHEK2 deficiency.

CHEK2 is considered to be involved in homologous recombination repair (HRR). Individuals who have germline pathogenic variants (gPVs) in CHEK2 are at increased risk to develop breast cancer and likely other primary cancers. PARP inhibitors (PARPi) have been shown to be effective in the treatment of cancers that present with HRR deficiency-for example, caused by inactivation of BRCA1/2. However, clinical trials have shown little to no efficacy of PARPi in patients with CHEK2 gPVs. Here, we show that both breast and non-breast cancers from individuals who have biallelic gPVs in CHEK2 (germline CHEK2 deficiency) do not present with molecular profiles that fit with HRR deficiency. This finding provides a likely explanation why PARPi therapy is not successful in the treatment of CHEK2-deficient cancers.