PAX1deficiency causes a syndromic form of SCID by altering differentiation of thymic epithelial cells and other pharyngeal pouch tissues.

Combined immunodeficiencies are a heterogeneous collection of primary immune disorders that exhibit defects in T cell development or function, along with impaired B cell activity even in light of normal B cell maturation. CARMIL2 (RLTPR) is a protein involved in cytoskeletal organization and cell migration, which also plays a role in CD28 co-signaling of T cells. Mutations in this protein have recently been reported to cause a novel primary immunodeficiency disorder with variable phenotypic presentations. Here, we describe seven patients from three unrelated, consanguineous multiplex families that presented with dermatitis, esophagitis, and recurrent skin and chest infections with evidence of combined immunodeficiency. Through the use of whole exome sequencing and autozygome-guided analysis, we uncovered two mutations not previously reported (p.R50T and p.L846Sfs) in CARMIL2. Real-time PCR analysis revealed that the biallelic frameshift mutation is under negative selection, likely due to nonsense-mediated RNA decay and leading to loss of detectable protein upon immunoblotting. Protein loss was also observed for the missense mutation, and 3D modeling suggested a disturbance in structural stability due to an increase in the electrostatic energy for the affected amino acid and surrounding residues. Immunophenotyping revealed that patient T_reg counts were significantly depressed, and that CD4⁺ T cells were heavily skewed towards the naïve status. CD3/CD28 signaling impairment was evidenced by reduced proliferative response to stimulation. This work broadens the allelic heterogeneity associated with CARMIL2 and highlights a deleterious missense alteration located outside the leucine-rich repeat of the protein, where all other missense mutations have been reported to date.

Loss of function in genes required for telomere maintenance result in disorders known as telomeropathies, which are characterized by a pattern of symptoms including generalized and specific lymphocytopenias as well as very short telomere length and disease anticipation. Because human LARP7 is the most likely ortholog of the Tetrahymena p65 protein, which is required for telomerase activity in that organism, we investigated the effects of LARP7 silencing in human cells as well as in two distinct families with Alazami syndrome (loss of function of LARP7). Depletion of LARP7 caused a reduction in telomerase enzymatic activity and progressively shorter telomeres in human cancer cell lines. Alazami syndrome patients from two separate cohorts exhibited very short lymphocyte telomeres. Further, wild-type offspring of LARP7 mutant individuals also had very short telomeres, comparable to what is observed in telomerase (hTERT) mutant cohorts. Together, these experiments demonstrate that in addition to the readily apparent developmental disorder associated with LARP7 deficiency, an underlying telomeropathy exists even in unaffected siblings of these individuals.

The camptodactyly-arthropathy-coxa vara-pericarditis (CACP) syndrome is an autosomal recessive disorder caused by mutations in the PRG4 (Proteoglycan 4) gene. Manifestations vary across families as well as between affected individuals from the same family, with camptodactyly and arthropathy of the knees the most ubiquitous, while pericarditis is evident in only one-fifth of all reported cases. Thus far only eight pathogenic mutations have been described in this gene. We examined seven newly diagnosed childhood patients of this syndrome, hailing from four unrelated families of Saudi origin. Five novel mutations were uncovered, including four frameshift deletions and one nonsense mutation (c.923_924delAA, c.3125_3128delGAGT, c.3139_3140delAA, c.3276_3277delAA, c.4078A>T). No genotype/phenotype association was observed. Because all mutations reported in CACP patients thus far predict premature truncation, we hypothesize that missense mutations are either not physiologically relevant, or that they trigger a clinical phenotype that is distinct from classical CACP. This is only the second published communication on PRG4 mutations, and increases the number of reported mutations for all ethnicities from 8 to 13, and for the Arab population specifically from one to six.

Asparagine synthetase deficiency (OMIM# 615574) is a very rare newly described neurometabolic disorder characterized by congenital microcephaly and severe global developmental delay, associated with intractable seizures or hyperekplexia. Brain MRI typically shows cerebral atrophy with simplified gyral pattern and delayed myelination. Only 12 cases have been described to date. The disease is caused by homozygous or compound heterozygous mutations in the ASNS gene on chromosome 7q21. Family 1 is a multiplex consanguineous family with five affected members, while Family 2 is simplex. One affected from each family was available for detailed phenotyping. Both patients (Patients 1 and 2) presented at birth with microcephaly and severe hyperekplexia, and were found to have gross brain malformation characterized by simplified gyral pattern, and hypoplastic cerebellum and pons. EEG showed no epileptiform discharge in Patient 2 but multifocal discharges in patient 1. Patient 2 is currently four years old with severe neurodevelopmental delay, quadriplegia and cortical blindness. Whole exome sequencing (WES) revealed a novel homozygous mutation in ASNS (NM_001178076.1) in each patient (c.970C > T:p.(Arg324*) and c.944A > G:p.(Tyr315Cys)). Our results expand the mutational spectrum of the recently described asparagine synthetase deficiency and show a remarkable clinical homogeneity among affected individuals, which should facilitate its recognition and molecular confirmation for pertinent and timely genetic counseling.

Mutations in KIF7, the gene that encodes a component of the kinesin complex of anterograde intraflagellar transport in the cilia, have been reported to cause a range of phenotypes including hydrolethalis, acrocallosal syndrome and Joubert syndrome. In a cohort of patients with various neurogenetic phenotypes, we identified novel KIF7 mutations in two families that span the known phenotypic spectrum of KIF7-related disorders. Surprisingly, we also identified a novel truncating KIF7 mutation in a third consanguineous family, in which the index presented with intellectual disability but no overt signs of ciliopathy, and his brain magnetic resonance imaging revealed an isolated dysgenesis of corpus callosum. This small cohort contributes novel pathogenic alleles of KIF7 and suggests that KIF7-related phenotypes can include isolated dysgenesis of corpus callosum with intellectual disability, thus expanding the range of phenotypes that warrant sequencing of this gene.