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Generalized arterial calcification of infancy (GACI) is a rare autosomal-recessive disease characterized by extensive arterial calcification in infancy, with clinical manifestations such as arterial stenoses and heart failure. The ENPP1 inactivation mutation has been identified as a potential defect in most of the cases of GACI, while mutations in ABCC6 are demonstrated in patients who are genotyped as pseudoxanthoma elasticum and only limited cases of GACI are reported. Whole-exome sequencing was applied for the detection of pathogenic variants. Copy-number variants of pathogenic genes were also evaluated through a bioinformatic process and were further validated by real-time quantitative PCR. In this report, we described the clinical information and treatment of a patient with extensive arterial calcification. We have identified the underlying cause as biallelic mutations in ABCC6 (NM_00117: exon30, c.4223_4227dupAGCTC p.(Leu1410Serfs*56)) and a unique exonic deletion that spans from the first to the fourth exons of ABCC6 (chr16:16313388-16330869)). This discovery was made by utilizing a combined genetic testing approach. With the review of previously reported GACI patients with ABCC6 mutation, our work contributed to enriching the mutation spectrum of GACI and providing further information on this rare form of inherited disorder. [ABSTRACT FROM AUTHOR]

Multiple synostoses syndromes (SYNS) are a group of rare genetic bone disorders characterized by multiple joint fusions. We previously reported an SYNS4‐causing GDF6 c.1330 T > A (p.Tyr444Asn) mutation, which reduced Noggin‐induced GDF6 inhibition and enhanced SMAD1/5/8 signaling. However, the mechanisms by which GDF6 gain‐of‐function mutation alters joint formation and the comprehensive molecular portraits of SYNS4 remain unclear. Herein, we introduce the p.Tyr443Asn (orthologous to the human GDF6 p.Tyr444Asn) mutation into the mouse Gdf6 locus and report the results of extensive phenotype analysis, joint development investigation, and transcriptome profiling of Gdf6 p.Tyr443Asn limb buds. Gdf6 p.Tyr443Asn knock‐in mice recapitulated the morphological features of human SYNS4, showing joint fusion in the wrists, ankles, phalanges, and auditory ossicles. Analysis of mouse embryonic forelimbs demonstrated joint interzone formation defects and excess chondrogenesis in Gdf6 p.Tyr443Asn knock‐in mice. Further, RNA sequencing of forelimb buds revealed enhanced bone formation and upregulated bone morphogenetic protein (BMP) signaling in mice carrying the Gdf6 p.Tyr443Asn mutation. Because tightly regulated BMP signaling is critical for skeletal development and joint morphogenesis, our study shows that enhancing GDF6 activity has a significant impact on both prenatal joint development and postnatal joint maintenance. © 2023 American Society for Bone and Mineral Research (ASBMR). [ABSTRACT FROM AUTHOR]

Background: Targeted gene capture and next‐generation sequencing (NGS) has been widely utilized as a robust and cost‐effective approach for detecting small variants among a group of disease genes. Copy number variations (CNV) can also be inferred from the read‐depth information but the accuracy of CNVs called from panel‐based NGS data has not been well evaluated. Methods: Sequencing data were acquired from patients underwent routine clinical targeted panel sequencing testing. Pathogenic CNVs detected from targeted panel sequencing data were evaluated using CNVs generated by two clinical accepted platforms, namely chromosome microarray analysis (CMA) and multiple ligation‐dependent probe amplification (MLPA) as benchmarks. CNVkit was used in our study to call CNVs from sequencing data using read‐depth information. CMA and MLPA tests were used to confirm and further assess the size and breakpoints of CNVs. Results: The size of CNVs detected using panel‐based NGS data are over 300 kb. The sizes of CNVs detected are slightly larger (102.3% on average) using the NGS platform than using the CMA platform, and the size accuracy improved as the size of variants increases. The breakpoints of CNVs detected using NGS data are quite close (within 2.3% of margin) to the breakpoints detected by CMA. CNVs on sex chromosomes, however, are less concordant between NGS and CMA platforms. Conclusion: Copy number variations covering adequate exons on autosomes can be accurately detected using targeted panel sequencing data as using CMA. CNVs detected from sex chromosomes need further evaluation and validation. Except for exon‐level deletion/duplication and CNV on sex chromosome, our data support the use of panel‐based NGS data for routine clinical detection of pathogenic CNVs. Copy number variations (CNV) detection based on panel‐based sequencing was comprehensively evaluated with clinical patients' data using chromosomal microarray and multiple‐ligation probe amplification as standards. CNVs larger than 600 kb on autosomes can be accurately detected using targeted panel sequencing data as using chromosome microarray. CNVs detected from sex chromosomes need further evaluation and validation. [ABSTRACT FROM AUTHOR]

Background: Type II bare lymphocyte syndrome (BLS II) group A is a rare primary severe immunodeficiency caused by defects in CIITA, one of genes encoding transcriptional regulatory factors for MHC II molecules., Objective: To report a Chinese boy with mutation of CIITA., Methods: By reviewing the clinical data of the child and performing a literature search of BLS II group A., Results: The patient was presented with persistent pneumonia, chronic diarrhea, urinary tract infection, rash, failure to thrive and special facial characteristics. The patient carried novel mutations in CIITA (c.1243delC, p.R415fs*2 and c.3226C>T, p.R1076W) which were identified by next-generation sequencing and confirmed by Sanger sequencing., Conclusions: This study found novel mutations in the CIITA gene of BLS II, which complemented the mutation spectrum and contributed to the diagnosis, treatment, genetic counseling and prenatal diagnosis of BLS II.

Generalized arterial calcification of infancy (GACI) is a rare autosomal-recessive disease characterized by extensive arterial calcification in infancy, with clinical manifestations such as arterial stenoses and heart failure. The ENPP1 inactivation mutation has been identified as a potential defect in most of the cases of GACI, while mutations in ABCC6 are demonstrated in patients who are genotyped as pseudoxanthoma elasticum and only limited cases of GACI are reported. Whole-exome sequencing was applied for the detection of pathogenic variants. Copy-number variants of pathogenic genes were also evaluated through a bioinformatic process and were further validated by real-time quantitative PCR. In this report, we described the clinical information and treatment of a patient with extensive arterial calcification. We have identified the underlying cause as biallelic mutations in ABCC6 (NM_00117: exon30, c.4223_4227dupAGCTC p.(Leu1410Serfs*56)) and a unique exonic deletion that spans from the first to the fourth exons of ABCC6 (chr16:16313388-16330869)). This discovery was made by utilizing a combined genetic testing approach. With the review of previously reported GACI patients with ABCC6 mutation, our work contributed to enriching the mutation spectrum of GACI and providing further information on this rare form of inherited disorder.