TRAPPC2L-related disorder: first homozygous protein-truncating variant and further delineation of the phenotype.

The TRAPP (TRAfficking Protein Particle) complexes are evolutionarily conserved tethering factors involved in the intracellular transport of vesicles for secretion and autophagy processes. Pathogenic variants in 8 genes (of 14) encoding TRAPP proteins are involved in ultra-rare human diseases, called TRAPPopathies. Seven of them are autosomal recessive neurodevelopmental disorders with overlapping phenotypes. Since 2018, two homozygous missense variants in TRAPPC2L have been reported in five individuals from three unrelated families with early-onset and progressive encephalopathy, with episodic rhabdomyolysis. We now describe the first pathogenic protein-truncating variant in the TRAPPC2L gene found at a homozygous state in two affected siblings. This report provides key genetic evidence invaluable to establishing the gene-disease relationship for this gene and important insights into the TRAPPC2L phenotype. Regression, seizures and postnatal microcephaly initially described are not constant features. Acute episodes of infection do not contribute to the neurological course. HyperCKaemia is part of the clinical picture. Thus, TRAPPC2L syndrome is mainly characterised by a severe neurodevelopmental disorder and a variable degree of muscle involvement, suggesting that it belongs to the clinical entity of rare congenital muscular dystrophies.

Germline AGO2 mutations impair RNA interference and human neurological development.

ARGONAUTE-2 and associated miRNAs form the RNA-induced silencing complex (RISC), which targets mRNAs for translational silencing and degradation as part of the RNA interference pathway. Despite the essential nature of this process for cellular function, there is little information on the role of RISC components in human development and organ function. We identify 13 heterozygous mutations in AGO2 in 21 patients affected by disturbances in neurological development. Each of the identified single amino acid mutations result in impaired shRNA-mediated silencing. We observe either impaired RISC formation or increased binding of AGO2 to mRNA targets as mutation specific functional consequences. The latter is supported by decreased phosphorylation of a C-terminal serine cluster involved in mRNA target release, increased formation of dendritic P-bodies in neurons and global transcriptome alterations in patient-derived primary fibroblasts. Our data emphasize the importance of gene expression regulation through the dynamic AGO2-RNA association for human neuronal development.

A new tool CovReport generates easy-to-understand sequencing coverage summary for diagnostic reports.

In order to properly interpret the results of a diagnostic gene panel sequencing test, gene coverage needs to be taken into consideration. If coverage is too low, an additional re-sequencing test is needed to make sure that a pathogenic variant is not missed. To facilitate the interpretation of coverage data, we designed CovReport, a novel easy-to-use visualization tool. CovReport generates a concise coverage summary that allows one-glance assessment of the sequencing test performance. Both gene-level and exon-level coverage can be immediately appreciated and taken into consideration for further medical decisions. CovReport does not require complex installation and can thus be easily implemented in any diagnostic laboratory setting. A user-friendly interface generates a graphic summary of coverage that can be directly included in the diagnostic report. In addition to a stand-alone version, we also provide a command line version of CovReport that can be integrated into any bioinformatics pipeline. This flexible tool is now part of routine sequencing analysis at the Department of Medical Genetics at La Timone Hospital (Marseille, France). CovReport is available at http://jdotsoft.com/CovReport.php. It is implemented in Java and supported on Windows, Mac OS X and Linux.

SATB2-associated syndrome: first report of a gonadal and somatic mosaicism for an intragenic copy number variation.

Gonadal mosaicism has been reported in a variety of dominant or X-linked conditions and should be considered in all cases of apparent de-novo variation. Recently, some cases of supposed parental germline mosaicism have been shown to result from low-level somatic mosaicism. In most of the cases, mosaicism has been reported for pathogenic single nucleotide variants with only a few cases of copy number variation mosaicism described so far. Herein, we present the first case of parental somatic and gonadal copy number variation mosaicism in the SATB2 gene. We report three brothers presenting with the SATB2-associated syndrome. They all carry the same 121-kb heterozygous intragenic deletion of SATB2. Parental somatic mosaicism was detected by array-comparative genomic hybridization on a maternal blood sample and confirmed by Fluorescence in situ hybridization analysis on blood and buccal cells. This clinical report highlights the importance of investigating for parental somatic mosaicism to estimate the proper recurrence risk for subsequent pregnancy.

Complex Compound Inheritance of Lethal Lung Developmental Disorders Due to Disruption of the TBX-FGF Pathway.

Primary defects in lung branching morphogenesis, resulting in neonatal lethal pulmonary hypoplasias, are incompletely understood. To elucidate the pathogenetics of human lung development, we studied a unique collection of samples obtained from deceased individuals with clinically and histopathologically diagnosed interstitial neonatal lung disorders: acinar dysplasia (n = 14), congenital alveolar dysplasia (n = 2), and other lethal lung hypoplasias (n = 10). We identified rare heterozygous copy-number variant deletions or single-nucleotide variants (SNVs) involving TBX4 (n = 8 and n = 2, respectively) or FGF10 (n = 2 and n = 2, respectively) in 16/26 (61%) individuals. In addition to TBX4, the overlapping ∼2 Mb recurrent and nonrecurrent deletions at 17q23.1q23.2 identified in seven individuals with lung hypoplasia also remove a lung-specific enhancer region. Individuals with coding variants involving either TBX4 or FGF10 also harbored at least one non-coding SNV in the predicted lung-specific enhancer region, which was absent in 13 control individuals with the overlapping deletions but without any structural lung anomalies. The occurrence of rare coding variants involving TBX4 or FGF10 with the putative hypomorphic non-coding SNVs implies a complex compound inheritance of these pulmonary hypoplasias. Moreover, they support the importance of TBX4-FGF10-FGFR2 epithelial-mesenchymal signaling in human lung organogenesis and help to explain the histopathological continuum observed in these rare lethal developmental disorders of the lung.

An atypical autistic phenotype associated with a 2q13 microdeletion: a case report.

BACKGROUND: Autism spectrum disorders are serious neurodevelopmental disorders that affect approximately 1% of the population. These disorders are substantially influenced by genetics. Several recent linkage analyses have examined copy number variations associated with autism risk. Microdeletion of the 2q13 region is considered a pathogenic copy number variation. This microdeletion is involved in developmental delays, congenital heart defects, dysmorphism, and various psychiatric disorders, including autism spectrum disorders. There are only 34 reported cases with this chromosomal deletion, and five cases of autism spectrum disorders have been identified among them. The autistic phenotype associated with this microdeletion has never been described. CASE PRESENTATION: We describe the case of a 44-month-old Caucasian girl with the 2q13 microdeletion and autism spectrum disorders with global development delay but no associated organ anomalies. We examined the autistic phenotype using different workups and observed an atypical phenotype defined by relatively preserved relational competency and imitation abilities. CONCLUSIONS: The main contribution of this case report is the precise description of the autistic phenotype in the case of this deletion. We observed some atypical clinical features that could be markers of this genetic anomaly. We have discussed the pathophysiology of autism associated with this microdeletion and its incomplete penetrance and variable expressivity.

The role of CNVs in the etiology of rare autosomal recessive disorders: the example of TRAPPC9-associated intellectual disability.

INTRODUCTION: A large number of genes involved in autosomal recessive forms of intellectual disability (ID) were identified over the past few years through whole-exome sequencing (WES) or whole-genome sequencing in consanguineous families. Disease-associated variants in TRAPPC9 were reported in eight multiplex consanguineous sibships from different ethnic backgrounds, and led to the delineation of the phenotype. Affected patients have microcephaly, obesity, normal motor development, severe ID, and language impairment and brain anomalies. PATIENTS: We report six new patients recruited through a national collaborative network. RESULTS: In the two patients heterozygous for a copy-number variation (CNV), the phenotype was clinically relevant with regard to the literature, which prompted to sequence the second allele, leading to identification of disease-associated variants in both. The third patient was homozygote for an intragenic TRAPPC9 CNV. The phenotype of the patients reported was concordant with the literature. Recent reports emphasized the role of CNVs in the etiology of rare recessive disorders. CONCLUSION: This study demonstrates that CNVs significantly contribute to the mutational spectrum of TRAPPC9 gene, and also confirms the interest of combining WES with CNV analysis to provide a molecular diagnosis to patients with rare Mendelian disorders.