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The interpretation of genetic testing results is subject to error. This observational study illustrates examples of pitfalls and challenges in interpretation of genetic testing results as reported by genetics professionals. We surveyed genetics professionals to describe interpretation challenges, the types of variants that were involved, and the reported clinical impact of misconception of a test result. Case studies were then collected from a select group to further explore potential causes of misunderstanding. A total of 83% of survey respondents were aware of at least one instance of genetic test misinterpretation. Both professionals with and without formal training in genetics were challenged by test reports, and variants of unknown significance were most frequently involved. Case submissions revealed that interpretation pitfalls extend beyond variant classification analyses. Inferred challenges in case submissions include lack of genetic counseling, unclear wording of reports, and suboptimal communication among providers. Respondents and case submitters noted that incorrect interpretation can trigger unnecessary follow-up tests and improperly alter clinical management. Further research is needed to validate and quantify large-scale data regarding challenges of genetic results interpretation.

The phenotypic variability associated with pathogenic variants in Lysine Acetyltransferase 6B (KAT6B, a.k.a. MORF, MYST4) results in several interrelated syndromes including Say‐Barber‐Biesecker‐Young‐Simpson Syndrome and Genitopatellar Syndrome. Here we present 20 new cases representing 10 novel KAT6B variants. These patients exhibit a range of clinical phenotypes including intellectual disability, mobility and language difficulties, craniofacial dysmorphology, and skeletal anomalies. Given the range of features previously described for KAT6B‐related syndromes, we have identified additional phenotypes including concern for keratoconus, sensitivity to light or noise, recurring infections, and fractures in greater numbers than previously reported. We surveyed clinicians to qualitatively assess the ways families engage with genetic counselors upon diagnosis. We found that 56% (10/18) of individuals receive diagnoses before the age of 2 years (median age = 1.96 years), making it challenging to address future complications with limited accessible information and vast phenotypic severity. We used CRISPR to introduce truncating variants into the KAT6B gene in model cell lines and performed chromatin accessibility and transcriptome sequencing to identify key dysregulated pathways. This study expands the clinical spectrum and addresses the challenges to management and genetic counseling for patients with KAT6B‐related disorders., We describe 20 new cases harboring the KAT6B spectrum of disorders, which range from Say‐Barber‐Biesecker‐Young‐Simpson (SBBYSS) to Genitopatellar (GPS) syndrome or an intermediate phenotype. In our holistic approach, we expand the genotypic and phenotypic spectrum of KAT6B spectrum of disorders. Furthermore, we provide extensive clinical phenotyping, explore the impact of genetic counseling for these complex syndromes, and examine molecular mechanisms in RNA‐seq data in an in vitro cell model of truncating KAT6B mutations.

Autosomal recessive osteopetrosis has a variable presentation, most commonly including failure to thrive, hypocalcemia, seizures, hepatosplenomegaly, hydrocephalus, vision or hearing loss, and cytopenias. Multiple symptoms are usually seen at presentation. The variability of presentation often delays diagnosis and subsequent treatment. Here, we present a case of an infant with this condition who initially presented with triventricular hydrocephalus with Chiari I malformation. This alone is not a common presentation of this disease, and we present this case to highlight autosomal recessive osteopetrosis as a potential diagnosis in infants presenting with hydrocephalus and discuss the other associated symptoms, management, and prognosis of this condition.The patient was a full-term infant with a routine newborn period. At 6 months, the infant had macrocephaly and frontal bossing with a bulging fontanelle. She was found to have hydrocephalus with moderate ventriculomegaly involving the third and lateral ventricles with an associated Chiari 1 malformation. The infant was asymptomatic at the time. The infant was promptly referred to neurosurgery and underwent an uncomplicated ventriculoperitoneal shunt placement. Post-operative X-rays showed increased density of the skull with other bone changes suggestive of autosomal recessive osteopetrosis. Subsequent lab work and imaging studies were consistent with this condition. The diagnosis was confirmed by genetic testing, and the patient has undergone treatment with hematopoietic stem cell transplant.Hydrocephalus is a common feature of this condition, typically seen in conjunction with other systemic symptoms and laboratory findings. Our patient had a limited initial presentation of triventricular hydrocephalus with Chiari I malformation and was otherwise clinically asymptomatic. There is limited literature of such a presentation, and we highlight this case to increase awareness, as timely diagnosis of these patients is critical for treatment and future outcomes.

Many congenital heart diseases (CHD) are associated with genetic defects. Children with complex CHD often have heart failure requiring heart transplant. Given the broad spectrum of genetic pathologies and dearth of transplants performed in these children, little is known regarding their outcomes.We conducted a retrospective review of heart transplants performed at a high-volume center from 2007 to 2021. Patients were separated into pathogenic molecular and copy number variants, aneuploidies, and variants of uncertain significance, and compared with patients without known genetic diagnoses. Variables included genetic diagnoses, bridge-to-transplant approach, preoperative comorbidities, operative characteristics, and postoperative complications. Outcomes included intensive care unit-free days to 28 days, hospital mortality, survival, rejection, retransplantation, and educational status at latest follow-up.In all, 223 patients received transplants over the study period: 9.9% (22 of 223) had pathogenic molecular variants; 4.5% (10 of 223) had copy number variants; 1.8% (4 of 223) had aneuploidies; and 9% (20 of 223) had variants of uncertain significance. The most common anomalies were Turner syndrome (n = 3) and 22q11.2 deletion syndrome (n = 2). Children with aneuploidies had higher rates of hepatic dysfunction and hypothyroidism, whereas children with pathogenic copy number variants had higher rates of preoperative gastrostomy and stroke. Children with aneuploidies were intubated longer after transplant, with greater need for reintubation, and had the fewest intensive care unit-free days. Mortality and mean survival did not differ. At median follow-up of 4.4 years (range, 1.9 to 8.8), 89.7% of survivors (26 of 29) with pathogenic anomalies were attending or had graduated school.Despite more preoperative comorbidities, midterm outcomes after heart transplant in children with genetic syndromes and disorders are promising.

Congenital hearing loss is a common cause of morbidity in early childhood. There are multiple reasons for congenital hearing impairment, with genetic contribution becoming increasingly recognized. Sensorineural hearing loss has classically been viewed as either syndromic or non-syndromic. With the advent of DNA sequencing technology such as NextGen sequencing, a subcategory has arisen, that of non-syndromic mimics (NSM)s. NSMs present initially as isolated hearing loss but as the patient ages other phenotypes become evident. Early diagnosis of these conditions is imperative as patients may suffer significant morbidity and mortality from complications from their hearing loss syndrome. An example is QT prolongation in Jervell and Lange-Nielsen Syndrome. The need for genetic testing and proper genetic counseling is necessary for patients with hearing loss and testing should be done as early in life as possible.

Repeated presentations of a rare symptom in a patient should make a physician stop and evaluate for rare conditions. This is a report of a teenager with multiple episodes of rhabdomyolysis and weakness. He was eventually diagnosed as having McArdle muscular dystrophy, or glycogen storage disease type V. His rhabdomyolysis has been severe, with a creatinine kinase level of >320,000 U/L, myoglobinuria, transaminitis, and elevated bilirubin. He has a low threshold for triggering rhabdomyolysis, such as doing an hour of aerobic exercise 2 days in a row. McArdle disease is a glycogen storage disorder in which the skeletal muscle cannot convert glycogen to glucose. Unlike other glycogen storage disorders, McArdle muscular dystrophy only affects the skeletal muscle, sparing the brain and visceral organs, leading to a vague phenotype. These patients have exercise intolerance, muscle cramps, and rhabdomyolysis. Many patients report loading with simple carbohydrates before exercise, as they have learned that this can increase their stamina. The vague symptoms can lead to decades of delay in diagnosis and significant mismanagement. Rhabdomyolysis is the most dangerous sign of McArdle disease, and it can lead to acute kidney injury, resulting in renal failure requiring dialysis in the severest cases.Rhabdomyolysis has numerous causes, but when it is recurrent, especially with seemingly insignificant triggers, one needs to develop a broader differential and pursue advanced testing. This testing can include specific exercise tests, genetic sequencing, and muscle biopsy. This case report will guide the clinician through the process of evaluating recurrent rhabdomyolysis, working through the differential diagnosis and testing options.1.