The diagnostic yield of genetic and metabolic investigations in syndromic and nonsyndromic patients with autism spectrum disorder, global developmental delay, or intellectual disability from a dedicated neurodevelopmental disorders genetics clinic.

First-tier genetic investigations for patients with neurodevelopmental disorders (NDDs) may include chromosomal microarray, Fragile X testing, and screening for inherited metabolic diseases, but most remain undiagnosed upon completion of testing. Here, we report the diagnostic yields of genetic testing for 537 patients with at least one of autism spectrum disorder, global developmental delay, and/or intellectual disability. Patients were assessed in a single neurodevelopmental genetics clinic, and each underwent a standardized history and physical examination. Each patient was characterized as syndromic or nonsyndromic based on clinical features. Our results demonstrate that multigene sequencing (with an NDD gene panel or exome) had a higher diagnostic yield (8%; 95% confidence interval [CI]: 5%, 13%) than chromosomal microarray and Fragile X testing combined (4%; 95% CI: 3%, 7%). Biochemical screening for inherited metabolic diseases had a diagnostic yield of zero. The diagnostic yield of genetic testing was significantly higher for syndromic patients than for nonsyndromic patients (odds ratio [OR] 3.09; 95% CI: 1.46, 6.83) and higher for female patients than for male (OR 3.21; 95% CI: 1.52, 6.82). These results add to the growing evidence supporting a comprehensive genetic evaluation that includes both copy number analysis and sequencing of known NDD genes for patients with NDDs.

Further clinical delineation of microcephaly-capillary malformation syndrome.

Microcephaly-Capillary Malformation syndrome (MIC-CAP) is a rare genetic disorder reported in 18 individuals to date. The clinical features typically include microcephaly, multiple cutaneous capillary malformations, seizures, neurologic impairment, and global developmental delay. Currently, there is little published information about the natural history and long-term outcomes for individuals with MIC-CAP. In this report, we provide follow up on two previously published patients and describe four new patients. The included patients highlight increased variability in the clinical spectrum and provide novel information regarding medical complications and recurrent variants.

Symptomatic mosaicism for a novel FBN1 splice site variant in a parent causing inherited neonatal Marfan syndrome.

Neonatal Marfan syndrome is a severe, early onset presentation of pathogenic variants in FBN1. Because of the significant cardiac involvement and early mortality, nearly all reported cases have been de novo, and the disorder has not been documented to be inherited from a symptomatic parent. Here, we present a female infant with neonatal Marfan syndrome who was born to a father with Marfan syndrome. Prior to the birth of his daughter, the father had been found to have an FBN1 missense variant of uncertain clinical significance. Initial familial variant testing of the infant did not reveal the same missense variant, but Sanger sequencing of FBN1 subsequently identified a pathogenic splice site variant. The father was then found to have 10%-20% mosaicism for the same splice site variant.