Nicholas A. Borja

Background: This study characterized beliefs about hereditary susceptibility to cancer and desire to know about a genetic predisposition to cancer in a nationally representative survey of US adults. Methods: Adjusted regression models using weighted survey analysis of NCI HINTS 2020 data assessed predictors of how much respondents (1) believe genes that are inherited determine whether a person will develop cancer and (2) would want to know if they had a genetic change that increases their chance of getting cancer. Results: On average, respondents endorsed between “somewhat” and “a lot” for how much hereditary susceptibility determines cancer risk. Respondents believed that hereditary susceptibility to cancer, cardiovascular disease, and diabetes were similar (Means= 1.83-1.85, all p>0.6). Individuals who had health insurance (β=–0.42 - –0.37, p=0.017-0.021) and previously sought cancer information (β=–0.19, p<0.001) believed in greater hereditary susceptibility to cancer, whereas those who self-reported good health believed in less hereditary susceptibility to cancer (β=0.16, p=0.022). Individuals who believed in greater hereditary susceptibility to cancer (β=0.14, p=0.001), previously sought cancer information (β=–0.19, p=0.002), had a family history of cancer (β=–0.19, p=0.005), were less fatalistic (β=–0.08, p=0.036), and were Hispanic (β=–0.25, p=.009) or Black (β=–0.47, p<0.001) endorsed a greater desire to know about a genetic predisposition to cancer. Conclusions: Efforts are needed to improve understanding of hereditary susceptibility, address fatalistic beliefs and misinformation, facilitate disclosure of family cancer history indicative of a potential genetic predisposition to cancer. Impact: Efforts are needed to improve access to genetic counseling and testing through education and targeted interventions.

LEO1 encodes a core subunit of the evolutionarily conserved RNA polymerase associated factor 1 complex (PAF1C), a key regulator of eukaryotic gene expression. While burden analyses suggest an association between rare LEO1 variants and an increased risk for neurodevelopmental disorder, the paucity of reported cases has prevented a definitive characterization of the resulting phenotype. We describe a male child with a novel de novo frameshift variant in LEO1 c.446dup (p.Asp149Gluf s*2) and undertake a comprehensive phenotype delineation of all previously reported patients. Developmental delay and autism spectrum disorder were core features common across patients with truncating variants, though rarer manifestations were also observed. This analysis supports LEO1 haploinsufficiency as a mechanism for this neurodevelopmental disorder. Further research is needed to more completely ascertain its associated features and penetrance. We nevertheless encourage its recognition as a definitive disease gene and inclusion in multigene panels.

Kabuki Syndrome (KS) is a rare multiple congenital anomaly syndrome originally described in 1981 by Japanese clinicians. KS belongs to the family of chromatinopathies, a group of disorders characterized by abnormalities in chromatin regulation due to germline mutations in the KMT2D or KDM6A genes. KS is characterized by five cardinal manifestations: (1) postnatal growth deficiency, (2) skeletal anomalies, (3) dermatoglyphic anomalies - including persistent fetal pads, (4) mild-to-moderate intellectual disability, and (5) typical facial features. Ocular abnormalities have been reported in more than one-third of patients with KS, but abnormalities involving the retina are rare. Currently, five accounts describing patients with KS and documented macular lesions exist within the literature. However, only two of these reports provide concurrent genetic confirmation. We describe the unique case of a female infant with molecularly confirmed KS due to a novel pathogenic variant in KMT2D who presented with retinopathy of prematurity (ROP) and bilateral macular lesions. Although our patient accounts for the sixth known case of foveal lesions associated with KS, she represents the third molecularly confirmed case of a de novo, nonsense KMT2D variant with macular abnormalities. In silico analysis with the prediction program MutationTaster found the mutation to be deleterious. Genetic testing, along with ophthalmologic examination and multimodal imaging, are indispensable tools for physicians, especially when confronted with patients suspected of having KS. When effectively used together, these tools can facilitate vision-preserving strategies.

Introduction: Nevoid basal cell carcinoma syndrome (NBCCS) is a rare autosomal dominant disorder classically associated with multiple basal cell carcinomas, odontogenic keratocysts and skeletal anomalies. However, its significant phenotypic heterogeneity often delays the diagnosis. Here, we undertake the first comprehensive characterisation of NBCCS and congenital urinary tract anomalies. Methods: Clinical evaluation followed by genetic testing was performed on a proband with congenital hydronephrosis due to ureteropelvic obstruction. Then, a cohort of patients with molecularly confirmed NBCCS evaluated at a single institution was analysed, followed by a comprehensive review of the literature. Results: The novel, non-canonical splice-site variant c.349+4 delA in PTCH1 was detected in a proband, with RNA analysis confirming exon 2 skipping. Of the additional nine NBCCS cases examined at our institution, a second proband with a nonsense variant in PTCH1 was identified with renal agenesis and a bladder diverticulum. A literature review then yielded 11 case reports of patients with congenital urinary tract anomalies, most frequently renal agenesis. Discussion: Congenital urinary tract anomalies are a variable finding in NBCCS. Renal ultrasound may be warranted at the time of initial diagnosis, if not previously performed. Moreover, PTCH1 should be included in multigene panels that assess for congenital urinary tract disorders.

Sex chromosome aneuploidies (SCA) such as Turner, Klinefelter, Jacobs, and Trisomy X syndromes are prevalent genetic disorders with well-established phenotypes. Challenges persist, however, in determining the need for further genetic evaluation in cases of affected individuals exhibiting atypical symptoms. The present study retrospectively examined 54 pediatric patients with an SCA diagnosis at a single institution between January 2015 and December 2023. Twelve patients (22.2%) exhibited a discordant phenotype, of which five were confirmed to have a distinct monogenic disorder, a diagnostic rate of 41.7%. The monogenic conditions identified included DNAH5-related primary ciliary dyskinesia, Burn-McKeown syndrome, Tatton-Brown-Rahman syndrome, SETD1B-related neurodevelopmental disorder, and SET-related disorder. The median age at SCA diagnosis was 3.5 months versus 7.0 years for the second genetic condition, indicating significant diagnostic delays. Our findings highlight the importance of comprehensive genetic evaluation in pediatric patients with SCA who exhibit atypical phenotypes.

KIF21A encodes a kinesin motor protein associated with isolated congenital fibrosis of the extraocular muscles (CFEOM), which occurs when the autoinhibitory interaction between its motor and third coiled-coil domains is disrupted. In this study, we describe a female child who is heterozygous for a novel de novo missense variant in KIF21A p.Leu664Pro, located in the second coiled-coil domain that was absent in her unaffected parents and in healthy population cohorts. She presented with progressive peripheral neuropathy, hypoplasia of the corpus callosum and strabismus in the absence of CFEOM. Protein modelling predicts that the KIF21A variant leads to significant alterations in its structure as well as binding with TUBB3. Co-immunoprecipitation data was consistent with decreased binding of KIF21A p.Leu664Pro to TUBB3 in vitro compared with reference. Taken together, we delineate a KIF21A-related phenotype defined by progressive peripheral neuropathy, brain anomalies, developmental delay and comitant strabismus potentially stemming from the disruption of the interaction between KIF21A and TUBB3.