American Journal of Medical Genetics Part A最新文献

Mucopolysaccharidosis type I (MPS I), a lysosomal disorder caused by variants in IDUA, was added to the Recommended Uniform Screening Panel for newborn screening in 2016. Positive screening results for MPS I are commonly due to variants known as "pseudodeficiency alleles," which decrease in vitro alpha-L-iduronidase enzyme activity but are thought to provide sufficient in vivo activity. Despite the historic assumption that these variants are biologically benign, the possibility that they could give rise to complex, multigenic, or attenuated phenotypes has not been systemically evaluated in adults. We completed a retrospective matched cohort study using a hospital-based biorepository with data from 65,309 participants, we identified 1803 individuals harboring homozygous IDUA pseudodeficiency alleles. Using electronic medical records (EMR), we compared the prevalence of features of MPS I in participants with homozygous pseudodeficiency alleles to a cohort of matched control participants. We found no clinically relevant significant differences between cases and controls nor genotype-phenotype associations across four alleles. These findings provide empiric support that adults with homozygous IDUA pseudodeficiency alleles are unlikely to develop mild symptoms of disease compared with controls. This study provides a proof-of-concept model for other nonclassical disease variants related to other inherited metabolic disorders, which is necessary as newborn screening expands.

T-box transcription factors are a group of evolutionarily conserved T-box-containing regulators of mesoderm specification and development. Heterozygous single nucleotide variants (SNVs) or copy-number variant (CNV) deletions involving dosage-sensitive TBX4 have been associated with pulmonary arterial hypertension (PAH), ischiocoxopodopatellar syndrome with or without PAH, and lethal lung developmental disorders (LLDDs), including acinar dysplasia (AcDys), congenital alveolar dysplasia (CAD), and other unspecified primary pulmonary hypoplasias. Loss- and gain-of-function variants have been proposed to cause pediatric PAH and LLDDs, and adult forms of PAH, respectively. Of more than 50 missense SNVs scattered across the entire TBX4, only three have been reported in patients with LLDDs, all mapping to the T-box domain. Here, we report a recurrence of a pathogenic substitution Glu86Lys identified in an unrelated patient with AcDys. In silico predictions of the conformational changes of TBX4 resulting from this and another substitution, Glu86Gln, suggest the loss of most intermolecular hydrogen bonds involving residue 86, including those with Tyr230 that directly interact with DNA. Functional assays on the TBX4 variants in fetal lung fibroblasts confirmed their deleterious character. We propose that Glu86 is critically involved in maintaining TBX4 structure and function essential for airway branching during early stages of human lung development. Substitutions of this residue may act in a dominant negative manner, leading to AcDys and CAD.

Snijders Blok-Campeau syndrome (SNIBCPS, OMIM#618205) is an autosomal dominant neurodevelopmental disorder attributed to pathogenic variants in the chromodomain helicase DNA binding protein 3 (CHD3) gene. To date, more than 100 individuals have been diagnosed with SNIBCPS. The syndrome is characterized by intellectual disability, global developmental delay, speech or language impediments, and dysmorphic features associated with macrocephaly. Additionally, affected individuals may exhibit behavioral issues, hypotonia, and autistic traits. A novel splicing variant (c.5590+1G > T) in the C-terminal 2 region of the CHD3 gene was identified in a patient predominantly exhibiting autistic characteristics. In vitro minigene splicing experiments conducted in HEK293 cells revealed that aberrant splicing resulted in the formation of a cryptic site 46 nucleotides downstream of the 5' splice site. This alteration was predicted to disrupt the reading frame by eliminating the physiological stop codon, consequently causing an extension in protein translation. Furthermore, an additional patient presenting with hypotonia, dysmorphic features, and global developmental delay was documented. This patient harbored a missense variant in the helicase C-terminal domain, c.3505C > T (p. Arg1169Trp). The pathogenic variant was anticipated to impact chromatin remodeling capacity and enzyme activity. Given the high prevalence of arginine residue pathogenic variants in the CHD3 protein and its notable propensity for binding and storing ATP molecules, intriguing insights into the potential effects of arginine residue pathogenic variants on phenotypes are provided. These findings contribute to a more comprehensive understanding of the genetic landscape of SNIBCPS while elucidating potential molecular mechanisms underlying the syndrome.

There is limited information on rationale for the current training structure within combined Pediatrics-Medical Genetics and Genomics Residency (MGG) residency programs. This study addresses the benefits and drawbacks of different training structures. Program Directors (PDs) and Associate PDs of combined Pediatrics-MGG residency programs were surveyed to evaluate perceived benefits of different structures and the relative importance of particular pediatric rotations for combined training. Programs varied in terms of how many times a typical resident transitioned between Pediatrics and MGG during training (range 4 to > 9). PDs varied in their opinions of which training structure would be most ideal for training a future Clinical Geneticist within a combined Pediatrics-MGG program. However, the majority of PDs indicated that consecutive training (completing two years of Pediatrics, followed by MGG) would support particular aims of training including continuity of patient care and research productivity. The top six out of twenty pediatric rotations that were ranked as most important in order of importance were neonatal intensive care, development and behavior pediatrics, term newborn, pediatric intensive care, neurology, and inpatient pediatric wards. Particular structures may facilitate distinct aims within training; however, there was not widespread consensus on which program structure would be best. Specific pediatric rotations were highlighted as very important, which could influence future curriculum development.

Here we describe a neonate exhibiting hypotonia, macrocephaly, renal cysts, and respiratory failure requiring tracheostomy and ventilator support. Genetic analysis via rapid genome sequencing (rGS) identified a loss on chromosome 4 encompassing polycystin-2 (PKD2) and a loss on chromosome 22 encompassing SH3 and Multiple Ankyrin Repeat Domains 3 (SHANK3), indicative of Phelan-McDermid syndrome. Further analysis via traditional karyotyping, Optical Genome Mapping (OGM), and PacBio long-read sequencing revealed a more complex landscape of chromosomal rearrangements in this individual, including a balanced 3;12 translocation, and an unbalanced 17;22 translocation. The proband's phenotypic presentation is thought to be the result of Phelan-McDermid syndrome and represents an expansion of the described phenotypes to include significant respiratory failure. This study underscores the challenges and importance of comprehensive genetic testing in elucidating complex presentations and highlights the need for complementary testing methods to overcome limitations in resolution.

Mowat-Wilson syndrome (MWS) is a complex disorder caused by heterozygous ZEB2 gene variations creating haploinsufficiency. The main clinical features are evolving facial dysmorphism, intellectual disability, eye and brain malformations, and various organ anomalies. Our study examines 10 Turkish patients, who had clinical diagnosis, underwent evaluation, clinical investigations, and genetic tests in multiple tertiary centers across Türkiye, and were molecularly diagnosed with MWS. Molecular analysis with sequencing techniques alongside array testing unveiled disease-causing variations in addition to novel variants, including two siblings with recurrent multiexon deletion. Clinical presentations varied, featuring neurodevelopmental delay and characteristic facial traits and organ malformations across all cases, alongside less frequently reported manifestations such as laryngomalacia or rocker bottom feet in addition to new features such as macroorchidism and osteoporosis. Our findings expand the genetic and phenotypical spectrum of MWS, and hint at potential implications of gonadal mosaicism. While establishing clear genotype-phenotype correlations poses challenges, comprehensive genetic testing remains pivotal for precise diagnosis and management. The study highlights the complexity of MWS genetics, with potential implications of gonadal mosaicism on recurrence. Further research is needed to elucidate mechanisms driving phenotypic variability, potential hotspots, and mechanisms for recurrent variations. We report on the largest cohort with MWS from Türkiye.

Hailey-Hailey disease (OMIM#169600) is an autosomal dominantly inherited genodermatosis characterized by erosions in the flexural areas of the body. Hailey-Hailey disease is caused by variants in ATP2C1, but for ~10% of the patients, no causative variant is found in the coding region of ATP2C1. We aimed to determine the genetic cause of Hailey-Hailey disease in a family without a variant in the coding areas of ATP2C1. By genome sequencing and analysis of all exon and intron sequences of ATP2C1, we identified the variant c.532-560 T>G (NM_014382.5) in intron 7 of ATP2C1. The variant is predicted by in silico tools to create a new deep intronic donor splice site. Segregation analysis detected the variant in the three affected family members. RNA sequencing confirmed that the variant creates a new deep intronic donor splice site that gives rise to an alternative exon. The identified deep-intronic variant in ATP2C1 is the likely cause of Hailey-Hailey disease. This is to our knowledge the first report of a deep-intronic variant as the cause of Hailey-Hailey disease, which shows that the analysis of the intronic sequences of ATP2C1 could increase the genetic diagnostic yield for Hailey-Hailey disease patients.

The RUBCN gene encodes a widely expressed protein called Rubicon, the main function of which is to negatively regulate macroautophagy. A single homozygous pathogenic variant of the RUBCN gene has been reported to date in two unrelated consanguineous Saudi families with spinocerebellar ataxia autosomal recessive 15 (OMIM#613516). This variant is responsible for the deletion of the highly conserved Rubicon Homology (RH) domain, which is important for the colocalization of Rubicon with Rab7 in the late endosome. In this work, we describe a female patient with childhood-onset epileptic encephalopathy and neurodevelopmental delay carrying a novel homozygous variant in RUBCN (NM_014687.3: c.2126 + 1G>A). A functional study of the RNA revealed that this variant completely abolishes the consensus donor site at the exon 14/intron 14 junction, resulting in the absence of expression of the reference transcript. Two alternative transcripts were expressed: a major transcript resulting from activation of an alternative exonic splice site and a minor transcript with skipping of exon 14. The two alternative transcripts lead to a shift in the reading frame introducing a premature stop codon. The resulting truncated protein lacks the RH domain, which may lead to defective endosomal trafficking as previously described. To our best knowledge, this is the first report of an impairment of RUBCN caused by a splice variant.