Bain type of X‐linked syndromic mental retardation in a male with a pathogenic variant in HNRNPH2

Heterogeneous nuclear ribonucleoproteins (hnRNPs) are RNA binding proteins, which aid in maturation, stabilization, and transport of mRNA. They have a significant role in cellular nucleic acid metabolism. The hnRNPs alter gene expression and are linked to various neurodegenerative disorders and cancers. Previously, six unrelated girls with developmental delay, intellectual disability, and hypotonia were found to have de novo heterozygous pathogenic missense variants in HNRNPH2, located on the X chromosome. A gain‐of‐function effect was proposed for the variant and it was thought to be lethal in males as no surviving males were identified. We describe a family with two affected siblings, one male and one female, with a known pathogenic variant in HNRNPH2, possibly due to maternal germline mosaicism.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/152580/1/ajmga61388.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/152580/2/ajmga61388_am.pd

Intrafamilial variability in syndromic microphthalmia type 5 caused by a novel variation in <i>OTX2</i>

<p><i>Background</i>: Anophthalmia/microphthalmia/coloboma (MAC) spectrum encompasses the most severe malformations of the eye. Together, they have an incidence of 2 in 10,000 births and can be unilateral or bilateral. These disorders are genetically heterogeneous.<i>Materials and methods</i>: We ascertained a large three-generation family with multiple members showing variable phenotypes of syndromic microphthalmia. Exome sequencing was performed for the proband and his affected maternal aunt. Targeted sequencing of <i>OTX2</i> gene was performed for other family members.<i>Result</i>: Variable clinical presentation in the form of unilateral microphthalmia and bilateral microphthalmia as well as nonpenetrance were noted. Exome sequencing revealed a novel heterozygous variant c.278G>T (p.W93L) in <i>OTX2</i> in the proband. All affected members as well as the unaffected mother of the proband carried the same variant.<i>Conclusion</i>: Syndromic microphthalmia due to mutations in <i>OTX2</i> can present with significant intrafamilial phenotypic variability.</p

Bi‐allelic missense variant, p.Ser35Leu in EXOSC1 is associated with pontocerebellar hypoplasia

RNA exosome is a highly conserved ribonuclease complex essential for RNA processing and degradation. Bi‐allelic variants in exosome subunits EXOSC3, EXOSC8 and EXOSC9 have been reported to cause pontocerebellar hypoplasia type 1B, type 1C and type 1D, respectively, while those in EXOSC2 cause short stature, hearing loss, retinitis pigmentosa and distinctive facies. We ascertained an 8‐months‐old male with developmental delay, microcephaly, subtle dysmorphism and hypotonia. Pontocerebellar hypoplasia and delayed myelination were noted on neuroimaging. A similarly affected elder sibling succumbed at the age of 4‐years 6‐months. Chromosomal microarray returned normal results. Exome sequencing revealed a homozygous missense variant, c.104C > T p.(Ser35Leu) in EXOSC1 (NM_016046.5) as the possible candidate. In silico mutagenesis revealed loss of a polar contact with neighboring Leu37 residue. Quantitative real‐time PCR indicated no appreciable differences in EXOSC1 transcript levels. Immunoblotting and blue native PAGE revealed reduction in the EXOSC1 protein levels and EXO9 complex in the proband, respectively. We herein report an individual with the bi‐allelic variant c.104C>T p.(Ser35Leu) in EXOSC1 and clinical features of pontocerebellar hypoplasia type 1. Immunoblotting and blue native PAGE provide evidence for the pathogenicity of the variant. Thus, we propose EXOSC1 as a novel candidate gene for pontocerebellar hypoplasia.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/167044/1/cge13928.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/167044/2/cge13928_am.pd