Novel blended SNRPE-related spliceosomopathy phenotype characterized by microcephaly and congenital atrichia.

Variants in genes encoding core components of the spliceosomes are associated with craniofacial syndromes, collectively called craniofacial spliceosomopathies. SNRPE encodes a core component of pre-mRNA processing U-rich small nuclear ribonuclear proteins (UsnRNPs). Heterozygous variants in SNRPE have been reported in six families with isolated hypotrichosis simplex in addition to one case of isolated non syndromic congenital microcephaly.

Insurance denials and diagnostic rates in a pediatric genomic research cohort.

Purpose: This study aimed to assess the amount and types of clinical genetic testing denied by insurance and the rate of diagnostic and candidate genetic findings identified through research in patients who faced insurance denials.

Methods: Analysis consisted of review of insurance denials in 801 patients enrolled in a pediatric genomic research repository with either no previous genetic testing or previous negative genetic testing result identified through cross-referencing with insurance prior-authorizations in patient medical records. Patients and denials were also categorized by type of insurance coverage.

Phenotypic expansion and variable expressivity in individuals with JARID2-related intellectual disability: A case series.

Loss of function variants in JARID2 were recently reported in 16 patients with a neurodevelopmental disorder characterized by delays, intellectual and learning disability, autism, behavioral abnormalities, and dysmorphic features. Most cases were de novo, with only one variant inherited from an affected parent. Here, we present seven additional individuals from five families with pathogenic or likely pathogenic JARID2 variants, confirming this gene-disease association and highlighting palatal abnormalities and heart defects as part of the phenotype.

TAB2 variants cause cardiovascular heart disease, connective tissue disorder, and developmental delay.

Congenital heart defects (CHD) are the most commonly occurring birth defect and can occur in isolation or with additional clinical features comprising a genetic syndrome. Autosomal dominant variants in TAB2 are recognized by the American Heart Association as causing nonsyndromic CHD, however, emerging data point to additional, extra-cardiac features associated with TAB2 variants. We identified 15 newly reported individuals with pathogenic TAB2 variants and reviewed an additional 24 subjects with TAB2 variants in the literature.

Heterozygous variants in ZBTB7A cause a neurodevelopmental disorder associated with symptomatic overgrowth of pharyngeal lymphoid tissue, macrocephaly, and elevated fetal hemoglobin.

By clinical whole exome sequencing, we identified 12 individuals with ages 3 to 37 years, including three individuals from the same family, with a consistent phenotype of intellectual disability (ID), macrocephaly, and overgrowth of adenoid tissue. All 12 individuals harbored a rare heterozygous variant in ZBTB7A which encodes the transcription factor Zinc finger and BTB-domain containing protein 7A, known to play a role in lympho- and hematopoiesis. ID was generally mild.

Syndromic neurodevelopmental disorder associated with de novo variants in DDX23.

The DEAD/DEAH box RNA helicases are a superfamily of proteins involved in the processing and transportation of RNA within the cell. A growing literature supports this family of proteins as contributing to various types of human disorders from neurodevelopmental disorders to syndromes with multiple congenital anomalies. This article presents a cohort of nine unrelated individuals with de novo missense alterations in DDX23 (Dead-Box Helicase 23).

Failure to thrive - an overlooked manifestation of KMT2B-related dystonia: a case presentation.

Background: KMT2B-related dystonia is a recently described form of childhood onset dystonia that may improve with deep brain stimulation. Prior reports have focused on neurologic features including prominent bulbar involvement without detailing general health consequences that may result from orolingual dysfunction. We describe a family with novel KMT2B mutation with several members with failure to thrive to highlight this non-neurologic, but consequential impact of mutation in this gene.

Occurrence and characterization of medulloblastoma in a patient with Curry-Jones syndrome.

Medulloblastoma in a Patient with Curry-Jones Syndrome with a mosaic variant, c.1234C > T (p.Leu412Phe), in SMO.

MAGEL2-related disorders: A study and case series.

Pathogenic MAGEL2 variants result in the phenotypes of Chitayat-Hall syndrome (CHS), Schaaf-Yang syndrome (SYS) and Prader-Willi syndrome (PWS). We present five patients with mutations in MAGEL2, including the first patient reported with a missense variant, adding to the limited literature. Further, we performed a systematic review of the CHS and SYS literature, assess the overlap between CHS, SYS and PWS, and analyze genotype-phenotype correlations among them.

Phenotypic spectrum associated with SPECC1L pathogenic variants: new families and critical review of the nosology of Teebi, Opitz GBBB, and Baraitser-Winter syndromes.

The SPECC1L protein plays a role in adherens junctions involved in cell adhesion, actin cytoskeleton organization, microtubule stabilization, spindle organization and cytokinesis. It modulates PI3K-AKT signaling and controls cranial neural crest cell delamination during facial morphogenesis. SPECC1L causative variants were first identified in individuals with oblique facial clefts.

Further delineation of Aymé-Gripp syndrome and use of automated facial analysis tool.

Aymé-Gripp syndrome (AGS) is an autosomal dominant multisystem disorder caused by specific heterozygous variants in MAF. The resulting aberrant protein shows impaired GSK-mediated MAF phosphorylation. AGS is characterized by congenital cataracts, sensorineural hearing loss, short stature, intellectual disability, and distinctive facial features with brachycephaly.

Biparental/androgenetic mosaicism in a male with features of overgrowth and placental mesenchymal dysplasia.

Biparental/androgenetic mosaicism is a rarely diagnosed condition in humans. It is typically ascertained prenatally on the basis of placental mesenchymal dysplasia. Fetal outcome can range from demise due to intrauterine growth retardation to term delivery.

Correction to: Incidental diagnosis of tuberous sclerosis complex by exome sequencing in three families with subclinical findings.

The published online version contain mistake in the author list. Instead of "A.M.

Incidental diagnosis of tuberous sclerosis complex by exome sequencing in three families with subclinical findings.

Tuberous sclerosis complex (TSC) is an autosomal-dominant neurocutaneous disorder characterized by lesions and benign tumors in multiple organ systems including the brain, skin, heart, eyes, kidneys, and lungs. The phenotype is highly variable, although penetrance is reportedly complete. We report the molecular diagnosis of TSC in individuals exhibiting extreme intra-familial variability, including the incidental diagnosis of asymptomatic family members.

Expanding the phenotype of feingold syndrome-2.

Feingold syndrome-2 has been recently shown to be caused by germline heterozygous deletions of MIR17HG with 10 reported patients to date. Manifestations common to both Feingold syndrome-1 and Feingold syndrome-2 include microcephaly, short stature, and brachymesophalangy; but those with Feingold syndrome-2 lack gastrointestinal atresias. Here we describe a 14-year-old male patient who presented to our Cardiovascular Genetics Clinic with a history of a bicuspid aortic valve with aortic stenosis, short stature, hearing loss, and mild learning disabilities.

Deletion of MAP2K2/MEK2: a novel mechanism for a RASopathy?

RASopathies are a class of genetic syndromes caused by germline mutations in genes encoding Ras/mitogen-activated protein kinase (Ras/MAPK) pathway components. Cardio-facio-cutaneous (CFC) syndrome is a RASopathy characterized by distinctive craniofacial features, skin and hair abnormalities, and congenital heart defects caused by activating mutations of BRAF, MEK1, MEK2, and KRAS. We define the phenotype of seven patients with de novo deletions of chromosome 19p13.