RESUMEN
PURPOSE: JARID2, located on chromosome 6p22.3, is a regulator of histone methyltransferase complexes that is expressed in human neurons. So far, 13 individuals sharing clinical features including intellectual disability (ID) were reported with de novo heterozygous deletions in 6p22-p24 encompassing the full length JARID2 gene (OMIM 601594). However, all published individuals to date have a deletion of at least one other adjoining gene, making it difficult to determine if JARID2 is the critical gene responsible for the shared features. We aim to confirm JARID2 as a human disease gene and further elucidate the associated clinical phenotype. METHODS: Chromosome microarray analysis, exome sequencing, and an online matching platform (GeneMatcher) were used to identify individuals with single-nucleotide variants or deletions involving JARID2. RESULTS: We report 16 individuals in 15 families with a deletion or single-nucleotide variant in JARID2. Several of these variants are likely to result in haploinsufficiency due to nonsense-mediated messenger RNA (mRNA) decay. All individuals have developmental delay and/or ID and share some overlapping clinical characteristics such as facial features with those who have larger deletions involving JARID2. CONCLUSION: We report that JARID2 haploinsufficiency leads to a clinically distinct neurodevelopmental syndrome, thus establishing gene-disease validity for the purpose of diagnostic reporting.
Asunto(s)
Discapacidad Intelectual , Trastornos del Neurodesarrollo , Haploinsuficiencia/genética , Heterocigoto , Humanos , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/genética , Trastornos del Neurodesarrollo/diagnóstico , Trastornos del Neurodesarrollo/genética , Fenotipo , Complejo Represivo Polycomb 2/genética , Síndrome , Secuenciación del ExomaRESUMEN
The forkhead box (FOX) transcription factors have roles in development, carcinogenesis, metabolism, and immunity. In humans FOXP1 mutations have been associated with language and speech defects, intellectual disability, autism spectrum disorder, facial dysmorphisms, and congenital anomalies of the kidney and urinary tract. In mice, Foxp1 plays critical roles in development of the spinal motor neurons, lymphocytes, cardiomyocytes, foregut, and skeleton. We hypothesized therefore that mutations of FOXP1 affect additional tissues in some humans. Supporting this hypothesis, we describe two individuals with novel variants of FOXP1 (NM_032682.5:c.975-2A>C and NM_032682.5:c.1574G>A) and additional features. One had a lung disease resembling neuroendocrine cell hyperplasia of infancy (NEHI), and the second had a skeletal disorder with undertubulation of the long bones and relapsing-remitting fevers associated with flushing and edema. Although attribution of these traits to mutation of FOXP1 requires ascertainment of additional patients, we hypothesize that the variable expression of these additional features might arise by means of stochastic developmental variation.
Asunto(s)
Trastorno del Espectro Autista/genética , Factores de Transcripción Forkhead/genética , Discapacidad Intelectual/genética , Trastornos del Lenguaje/genética , Enfermedades Pulmonares/genética , Proteínas Represoras/genética , Secuencia de Aminoácidos , Trastorno del Espectro Autista/diagnóstico por imagen , Femenino , Haploinsuficiencia , Humanos , Recién Nacido , Discapacidad Intelectual/diagnóstico por imagen , Trastornos del Lenguaje/diagnóstico por imagen , Pulmón/diagnóstico por imagen , Enfermedades Pulmonares/diagnóstico , Masculino , Modelos Moleculares , Mutación , Fenotipo , Dominios Proteicos , Alineación de Secuencia , Secuenciación del ExomaRESUMEN
BACKGROUND: Consent forms for exome and/or genome sequencing, collectively called genome-wide sequencing (GWS), frequently contain detailed information on complex topics such as sequencing analysis and incidental findings. Considering recent endeavors by the health care community to simplify GWS consent forms, it is important to gain stakeholders' perspectives on the content, length, and use of consent forms. METHODS: Thematic analysis was conducted on data obtained from focus groups with two participant cohorts: parents who previously provided consent for trio-based GWS as part of the translational pediatric GWS CAUSES Study, and genetic health care providers (HCP) who provide pre-test counseling for GWS. RESULTS: Genetic HCP indicated that consent forms cannot replace pre-test counseling, and as such, a simplified consent form focusing on the implications of GWS would be beneficial to both patients and HCP. Although parents' primary concerns varied when considering GWS, they all highly valued information. Parents also indicated the need for community and support after the return of GWS results. Both participant cohorts recommended that consent forms be available online and include an appendix for supplementary information. CONCLUSION: It is important to include both parents and HCP in the design of GWS consent forms, and also, to help connect families who have a shared diagnosis after the post-test counseling session.