Deficiencies of the early complement components of the classical pathway (CP) are well-documented in association with systemic lupus erythematosus (SLE) or SLE-like syndromes and severe pyogenic infections. Among these, complete C1s deficiency has been reported in nine cases so far. Here, we describe a 34-year-old male patient who presented with severe, recurrent infections since childhood, including meningitides with pneumococci and meningococci, erysipelas, subcutaneous abscess, and recurrent infections of the upper airways. The patient also exhibited adult-onset SLE, meeting 7/11 of the ACR criteria and 34 of the 2019 EULAR/ACR classification criteria, along with class IV-G (A) proliferative lupus nephritis (LN). A screening of the complement cascade showed immeasurably low CH50, while the alternative pathway (AP) function was normal. Subsequent determination of complement components revealed undetectable C1s with low levels of C1r and C1q, normal C3, and slightly elevated C4 and C2 concentrations. The patient had no anti-C1q antibodies. Renal biopsy showed class IV-G (A) LN with complement C1q positivity along the glomerular basement membranes (GBMs) and weak deposition of IgG, IgM, and complement C3 and C4 in the mesangium and GBM. In an ELISA-based functional assay determining C4d deposition, the patient\'s absent complement activity was fully restored by adding C1s. The genome of the patient was analyzed by whole genome sequencing showing two truncating variants in the C1S gene. One mutation was located at nucleotide 514 in exon 5, caused by a nucleotide substitution from G to T, resulting in a nonsense mutation from Gly172 (p.Gly172*). The other mutation was located at nucleotide 750 in exon 7, where C was replaced by a G, resulting in a nonsense mutation from Tyr250 (p.Tyr250*). Both mutations create a premature stop codon and have not previously been reported in the literature. These genetic findings, combined with the absence of C1s in the circulation, strongly suggest a compound heterozygote C1s deficiency in our patient, without additional defect within the complement cascade. As in a previous C1s deficiency case, the patient responded well to rituximab. The present case highlights unanswered questions regarding the CP\'s role in SLE etiopathogenesis.

Congenital short bowel syndrome (CSBS) is a rare condition characterized by an inborn shortening of bowel length with loss of intestinal functions, which often combines malrotation. CXADR-like membrane protein (CLMP) and filamin A (FLNA) gene mutations are the two major causes of this inherited defect. We presented two siblings with the older brother suffering from a laparotomy for bowel obstruction due to malrotation on the 17th day after birth. The younger sister encountered a laparotomy for lactobezoar at 6 months old. CSBS was diagnosed by measurement of the bowel length during the operations. Compound heterozygous CLMP mutations with the paternal allele harboring a long deletion across exon 3-5 and the maternal allele bearing a non-sense mutation of exon 3 (c.235C > T, p.Q79∗) were identified in both cases. They are the first reported familial CSBS caused by novel CLMP mutations in Taiwan.

Split hand/split foot malformation (SHFM) or ectrodactyly is characterized by a deep median cleft of the hand or foot, hypoplasia or aplasia of the metacarpals, metatarsals, and phalanges. It is a clinically and genetically heterogeneous group of limb malformations. This study aimed to identify the pathogenic variant in a consanguineous Pakistani family with autosomal recessive SHFM. Peripheral blood samples were obtained, DNA was extracted, WNT10B coding and noncoding regions were PCR amplified and Sanger sequencing was performed using workflow suggested by Thermo Fisher Scientific. A novel homozygous nonsense variant (c.1098C>A; p.Cys366*) was identified in the WNT10B gene in the index patients, which probably explains SHFM type 6 in this family in comparison with similar data from the literature.

Background: Severe 5,10-methylenetetrahydrofolate reductase (MTHFR) deficiency is a heterogeneous metabolic disorder inherited in an autosomal recessive manner. Pathogenic mutations in MTHFR gene have been associated with severe MTHFR deficiency. The clinical presentation of MTHFR deficiency is highly variable and associated with several neurological anomalies. Methods: Direct whole-exome sequencing (WES) was performed in all the five available individuals from the family, including the affected individual (III-7) using standard procedures. Results: We observed a proband (III-7) with an abnormality in the cerebral white matter, apnoea, and microcephaly. WES analysis identified a novel homozygous non-sense mutation (c.154C>T; p.Arg52*) in MTHFR gene that segregated with the disease phenotype within the family. Conclusion: We identified a novel non-sense mutation in MTHFR gene in a single Egyptian family with severe MTHFR deficiency. The present investigation is clinically important, as it adds to the growing list of MTHFR mutations, which might help in genetic counseling of families of affected children and proper genotype-phenotype correlation.

The constitutively expressed hyaluronic acid capsule is an important virulence factor of Streptococcus equi, the cause of equine strangles. Study of the genomic sequence of CF22caps-, a non-encapsulated mutant of S. equi CF22 generated by gamma (Co60) irradiation revealed a non-sense mutation in fasC (SEQ_0302), a sensor kinase gene in FasBCAX an operon with an important regulatory role in expression of streptococcal secreted virulence and matrix binding proteins. The mutation was associated with a significant (p < .05) decrease in transcription of hasA, the synthase gene essential for hyaluronic acid synthesis and, conversely, with small increases in transcription of skc, covR and seM. The early growth phase of CF22caps- was also delayed compared to the CF22caps+ parent. In contrast to the human pathogen, S. pyogenes, capsule synthesis in S. equi therefore appears to be controlled by FasBCAX and not by CovRS.

Introduction: Congenital heart diseases (CHDs) are structural cardiovascular malformations that arise from abnormal development of the heart during the prenatal life. Mutations in the TBX5 gene, encoding T-box transcription factor, are a major cause of CHD. To evaluate the TBX5 mutations in hotspot exons in sporadic pediatric patients with CHD phenotypes, analytical case/control study performed in an Iranian cohort of unrelated patients with clinical diagnosis of congenital heart malformations. Methods: We investigated TBX5 coding exons 4, 5, 6 and 7 in 95 sporadic patients with CHD phenotypes and compared to 82 healthy controls using PCR-SSCP and DNA sequencing approaches. Results: We report here on a novel and heterozygote Non-sense mutation in exon 5 of TBX5, E128X (G14742T), in two Iranian children. This mutation locates inside the T-box and both of pediatric patients carrying this novel mutation suffer from severe heart malformations. The G14742T mutation leads to the substitution of glutamic acid (E) by stop codon (X) at residue 128, an evolutionarily conserved position in T-box as well as in other species. The non-sense mutation of E128X was predicted to be pathogenic by Mutation Taster and Polyphen software programs. Conclusion: TBX5 E128X mutation results in a translational premature stop. This type of mutation results in a shortened protein that may function improperly and which cannot bind to other transcription factors; therefore, haploinsufficiency of TBX5 protein is presumably causing the severe cardiac malformations in these patients.