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Pathogenic variants in KMT2D are typically associated with Kabuki syndrome (KS), a rare multisystem disorder. KS is characterized by facial dysmorphisms, intellectual disability, skeletal and dermatoglyphic differences, and poor growth. Seventy percent of individuals with clinically diagnosed KS have a confirmed pathogenic variant in KMT2D or less commonly KDM6A. The majority of mutations found in KMT2D are de novo nonsense or frameshift, with deletions and duplications rarely reported in the literature. Here we present the case of near complete deletion of KMT2D in a college student with normal intelligence discovered via exome sequencing and EpiSign methylation testing. This case provides evidence that large deletions in KMT2D are compatible with normal intelligence and presents EpiSign as a method for discovering molecular causes of KS not identified by traditional molecular testing.

Contains fulltext : 291896.pdf (Publisher’s version ) (Closed access) AMOTL1 encodes angiomotin-like protein 1, an actin-binding protein that regulates cell polarity, adhesion, and migration. The role of AMOTL1 in human disease is equivocal. We report a large cohort of individuals harboring heterozygous AMOTL1 variants and define a core phenotype of orofacial clefting, congenital heart disease, tall stature, auricular anomalies, and gastrointestinal manifestations in individuals with variants in AMOTL1 affecting amino acids 157-161, a functionally undefined but highly conserved region. Three individuals with AMOTL1 variants outside this region are also described who had variable presentations with orofacial clefting and multi-organ disease. Our case cohort suggests that heterozygous missense variants in AMOTL1, most commonly affecting amino acid residues 157-161, define a new orofacial clefting syndrome, and indicates an important functional role for this undefined region.

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.

Mitogen-Activated Protein 3 Kinase 7 (MAP3K7, MIM 602614) encodes the ubiquitously expressed transforming growth factor β (TGF-β)–activated kinase 1 (TAK1), which plays a crucial role in many cellular processes. Variants in the MAP3K7 gene have been linked to 2 distinct disorders: frontometaphyseal dysplasia type 2 (FMD2, MIM #617137) and cardiospondylocarpofacial syndrome (CSCF, MIM #157800). The fact that different variants can induce 2 distinct phenotypes suggests a phenotype/genotype correlation, but no side-by-side comparison has been done thus far to confirm this. Here we significantly expand the cohort and the description of clinical phenotypes for individuals with CSCF and FMD2 who carry variants in MAP3K7. We show that in contrast to FMD2-causing variants, CSCF-causing variants in MAP3K7 have a loss-of-function effect. Additionally, patients with pathogenic variants in MAP3K7 are at risk for cardiac disease, have symptoms associated with connective tissue disease and we show overlap in clinical phenotypes of CSCF with Noonan syndrome. Together, we provide evidence for a molecular fingerprint of FMD2- versus CSCF-causing MAP3K7 variants and conclude that variants in MAP3K7 should be considered in the differential diagnosis of patients with syndromic congenital cardiac defects and/or cardiomyopathy, syndromic connective tissue disorders and in the differential diagnosis of Noonan syndrome.

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.

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.