Utilizing RNA and outlier analysis to identify an intronic splice-altering variant in AP4S1 in a sibling pair with progressive spastic paraplegia.

We report a likely pathogenic splice-altering AP4S1 intronic variant in two sisters with progressive spastic paraplegia, global developmental delay, shy character, and foot deformities. Sequencing was completed on whole-blood messenger RNA (mRNA) and analyzed for gene expression outliers after exome sequencing analysis failed to identify a causative variant. AP4S1 was identified as an outlier and contained a rare homozygous variant located three bases upstream of exon 5 (NC_000014.8(NM_007077.4):c.295-3C>A). Confirmed by additional RNA-seq, reverse-transcription polymerase chain reaction, and Sanger sequencing, this variant corresponded with exon 5, including skipping, altered isoform usage, and loss of expression from the canonical isoform 2 (NM_001128126.3). Previously, loss-of-function variants within AP4S1 were associated with a quadriplegic cerebral palsy-6 phenotype, AP-4 Deficiency Syndrome. In this study, the inclusion of mRNA-seq allowed for the identification of a previously missed splice-altering variant, and thereby expands the mutational spectrum of AP-4 Deficiency Syndrome to include impacts to some tissue-dependent isoforms.

EP300-related Rubinstein-Taybi syndrome: Highlighted rare phenotypic findings and a genotype-phenotype meta-analysis of 74 patients.

Pathogenic variants in the homologous and highly conserved genes-CREBBP and EP300-are causal for Rubinstein-Taybi syndrome (RSTS). CREBBP and EP300 encode histone acetyltransferases (HAT) that act as transcriptional co-activators, and their haploinsufficiency causes the pathology characteristic of RSTS by interfering with global transcriptional regulation. Though generally a well-characterized syndrome, there is a clear phenotypic spectrum; rare associations have emerged with increasing diagnosis that is critical for comprehensive understanding of this rare syndrome. We present 12 unreported patients with RSTS found to have EP300 variants discovered through gene sequencing and chromosomal microarray. Our cohort highlights rare phenotypic features associated with EP300 variants, including imperforate anus, retained fetal finger pads, and spina bifida occulta. Our findings support the previously noted prevalence of pregnancy-related hypertension/preeclampsia seen with this disease. We additionally performed a meta-analysis on our newly reported 12 patients and 62 of the 90 previously reported patients. We demonstrated no statistically significant correlation between phenotype severity (within the domains of intellectual disability and major organ involvement, as defined in our Methods section) and variant location and type; this is in contrast to the conclusions of some smaller studies and highlights the importance of large patient cohorts in characterization of this rare disease.

Correction: Expanding the clinical phenotype of individuals with a 3-bp in-frame deletion of the NF1 gene (c.2970_2972del): an update of genotype-phenotype correlation.

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Expanding the clinical phenotype of individuals with a 3-bp in-frame deletion of the NF1 gene (c.2970_2972del): an update of genotype-phenotype correlation.

PURPOSE: Neurofibromatosis type 1 (NF1) is characterized by a highly variable clinical presentation, but almost all NF1-affected adults present with cutaneous and/or subcutaneous neurofibromas. Exceptions are individuals heterozygous for the NF1 in-frame deletion, c.2970_2972del (p.Met992del), associated with a mild phenotype without any externally visible tumors. METHODS: A total of 135 individuals from 103 unrelated families, all carrying the constitutional NF1 p.Met992del pathogenic variant and clinically assessed using the same standardized phenotypic checklist form, were included in this study. RESULTS: None of the individuals had externally visible plexiform or histopathologically confirmed cutaneous or subcutaneous neurofibromas. We did not identify any complications, such as symptomatic optic pathway gliomas (OPGs) or symptomatic spinal neurofibromas; however, 4.8% of individuals had nonoptic brain tumors, mostly low-grade and asymptomatic, and 38.8% had cognitive impairment/learning disabilities. In an individual with the NF1 constitutional c.2970_2972del and three astrocytomas, we provided proof that all were NF1-associated tumors given loss of heterozygosity at three intragenic NF1 microsatellite markers and c.2970_2972del. CONCLUSION: We demonstrate that individuals with the NF1 p.Met992del pathogenic variant have a mild NF1 phenotype lacking clinically suspected plexiform, cutaneous, or subcutaneous neurofibromas. However, learning difficulties are clearly part of the phenotypic presentation in these individuals and will require specialized care.

Health Supervision for Children and Adolescents With Marfan Syndrome.

Marfan syndrome is a heritable connective tissue disorder that affects many different organ systems. In some cases, features of Marfan syndrome can be recognized at birth, but the majority will have manifestations that emerge throughout childhood and into adulthood. Significant morbidity and mortality are associated with this syndrome, and its features are best managed using a multidisciplinary approach. This clinical report is designed to assist the pediatrician in recognizing the features of Marfan syndrome as well as caring for the individual with Marfan syndrome to maximize their health and quality of life.

Two Cases of Preaxial Polydactyly of the Foot: Important Implications for Plastic Surgeons.

Although polydactyly is quite common in general, preaxial polydactyly of the foot is rare (0.4 per 10,000 patients) and specifically associated with certain congenital abnormalities and syndromes, which can include craniosynostosis, corpus callosum agenesis, and renal malformations. We present 2 recent cases of preaxial polydactyly of the foot that highlight the importance of maintaining a high level of suspicion for associated abnormalities in these patients. The first patient, who presented with supernumerary preaxial digits on both feet, pre- and postaxial polydactyly of the hands, was also macrocephalic and hyperteloric; this presentation strongly suggested a diagnosis of Greig cephalopolysyndactyly, a GLI3-variant syndrome. The second patient, who had 2 preaxial digits on one foot, was found to also have a horseshoe kidney, a malformation that has been associated with limb defects as part of an acrorenal syndrome. These cases emphasize the importance of a thorough clinical approach to patients with preaxial polydactyly of the foot. Although many patients with this anomaly may be well known to geneticists, a child may be referred to a plastic surgeon for reconstruction of what is thought to be an isolated cosmetic or local functional issue. Plastic surgeons should be aware of the complex nature of preaxial polydactyly of the foot and potential syndromic presentation.

Tissue Specificity in Trisomy 22 Mosaicism: A Tale of Caution for Interpretation of Chromosomal Microarray Results.

OBJECTIVES: While the complete form of trisomy 22 is seemingly incompatible with life, the mosaic form is a rare syndrome associated with developmental delays, intellectual disability, and dysmorphic features. Due in part to the difficulty of analyzing chromosomal mosaicism, many instances either go undiagnosed or have their diagnosis delayed. We report a case of mosaic trisomy 22 in a diamnionic-dichorionic twin with marked growth discordance and intra-uterine growth restriction, diagnosed in a 2-year-old with developmental delays, sensorineural hearing loss, cardiac and gastrointestinal abnormalities, and osteopenia of prematurity. Evaluation with a chromosomal oligonucleotide microarray with SNP analysis did not detect any copy number variants. Fibroblast metaphase karyotype analysis from a skin biopsy, however, showed trisomy 22 which was confirmed by FISH. Follow-up peripheral blood karyotype analysis and FISH studies revealed a normal male karyotype. This case highlights an instance where classical cytogenetics from two separate tissue types can provide a diagnosis that is more cost-effective than microarray analysis in assessing pediatric developmental delay. Trisomy 22 is the second most common aneuploidy in spontaneous miscarriages and has a nondescript and variable phenotype, especially in cases of mosaicism. As such, this condition may be underdiagnosed using the current recommended testing algorithm. Chromosomal microarray is considered first tier testing in an unrecognized phenotype with whole exome or whole genome sequencing, often performed on peripheral blood, as second tier testing. Diagnoses such as mosaic trisomy 22 suggest the second tier of testing in undiagnosed cases should also include a recommendation to look at alternative tissue types.

The Undergraduate Training in Genomics (UTRIG) Initiative: early & active training for physicians in the genomic medicine era.

Genomic medicine is transforming patient care. However, the speed of development has left a knowledge gap between discovery and effective implementation into clinical practice. Since 2010, the Training Residents in Genomics (TRIG) Working Group has found success in building a rigorous genomics curriculum with implementation tools aimed at pathology residents in postgraduate training years 1-4. Based on the TRIG model, the interprofessional Undergraduate Training in Genomics (UTRIG) Working Group was formed. Under the aegis of the Undergraduate Medical Educators Section of the Association of Pathology Chairs and representation from nine additional professional societies, UTRIG's collaborative goal is building medical student genomic literacy through development of a ready-to-use genomics curriculum. Key elements to the UTRIG curriculum are expert consensus-driven objectives, active learning methods, rigorous assessment and integration.

Familial unilateral ectopia lentis.

Ectopia lentis is almost always a bilateral condition, although it may be asymmetric in some cases of Marfan syndrome. Unilateral ectopia lentis has been associated with trauma and with intraocular tumors. We report two siblings with isolated unilateral ectopia lentis who had no evidence of underlying abnormality or of trauma.

Marshall-Smith syndrome: natural history and evidence of an osteochondrodysplasia with connective tissue abnormalities.

The Marshall-Smith syndrome (MSS) is a distinct malformation syndrome characterized by accelerated skeletal maturation, relative failure to thrive, respiratory difficulties, mental retardation, and unusual facies, including prominent forehead, shallow orbits, blue sclerae, depressed nasal bridge, and micrognathia. At least 33 cases have been reported in the literature, mostly as single case reports or small series. The purpose of the present study is to report on the clinical findings and natural history of MSS in five children and to review the features of three others previously reported, with particular attention to the skeletal and connective tissue findings. Our study demonstrates an increased rate of nontraumatic fractures and other bony and connective tissue abnormalities that support the hypothesis that MSS should be considered an osteochondrodysplasia. In addition, long-term survival beyond infancy is possible if respiratory problems are expectantly and aggressively managed.