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Introduction: Pathogenic biallelic RNPC3 variants cause congenital hypopituitarism (CH) with congenital cataracts, neuropathy, developmental delay/intellectual disability, primary ovarian insufficiency, and pituitary hypoplasia. Here, we aimed to evaluate the clinical and molecular characteristics of 2 patients with CH and neuropathy. Materials and Methods: Proband was evaluated by clinical, laboratory, and radiological exams, followed by exome sequencing (ES). Clinical investigation of an affected sibling and variant segregation in the family was performed by Sanger sequencing. A three-dimensional protein model study was conducted to predict the effect of the variant on the function of the RNPC3 peptide. Results: Proband was a 16-month-old girl who was referred for the evaluation of failure to thrive. Her height, weight, and head circumference were 55.8 cm (−7.6 SDS), 6.5 kg (−3.6 SDS), and 41.8 cm (−3.82), respectively. She had a developmental delay and intellectual disability. Central hypothyroidism, growth hormone, and prolactin deficiencies were identified, and MRI revealed pituitary hypoplasia. Electroneuromyography performed for the gait abnormality revealed peripheral neuropathy. A homozygous novel variant c.484C>T/p.(Pro162Ser) in the RNPC3 was detected in the ES. Her brother had the same genotype, and he similarly had pituitary hormone deficiencies with polyneuropathy. Conclusion: Expanding our knowledge of the spectrum of RNPC3 variants, and apprehending clinical and molecular data of additional cases, is decisive for accurate diagnosis and genetic counseling. [ABSTRACT FROM AUTHOR]

Background: Heterozygous relatives of ataxia‐telangiectasia (AT) patients are at an increased risk for certain AT‐related manifestations. We also show that there is an increase of infection frequency in parents of AT patients. Thus, we hypothesized that the parents might exhibit immune alterations similar to their affected children. Methods: Lymphocyte phenotyping to enumerate T‐ and B‐cell subsets was performed. Functional analyses included in vitro quantified γ‐H2AX, poly (ADP‐ribose) polymerase (PARP) and caspase‐9 proteins. Chromosomal instability was determined by comet assay. Results: We analyzed 20 AT patients (14F/6M), 31 parents (16F/15M), and 35 age‐matched healthy controls. The AT patients' parents exhibited low frequency of naive CD4+ T‐ (n = 14, 45%) and recent thymic emigrants (n = 11, 35%) in comparison with the age‐matched healthy donors. Interestingly, parents with low naive T cells also demonstrated high rate of recurrent infections (9/14, 64%). In comparison with age‐matched controls, parents who had recurrent infections and low naive T cells showed significantly higher baseline γ‐H2AX levels and H2O2‐induced DNA damage as well as increased cleaved caspase‐9 and PARP proteins. Conclusion: Parents of AT patients could present with recurrent infections and display cellular defects that mimic AT patients. The observed immunological changes could be associated with increased DNA double‐strand breaks. [ABSTRACT FROM AUTHOR]

Biallelic mutations in the TRAPPC12 gene are responsible for early-onset progressive encephalopathy with brain atrophy and spasticity (PEBAS). To date, three different allelic variants have been reported. Next-generation sequencing allowed discovery of unique alternations in this gene with different phenotypes. We report two patients carrying TRAPPC12 variants, one previously reported and one unknown mutation, with severe neurodevelopmental delay and brain atrophy. Standard clinical examination and cranial imaging studies were performed in these two unrelated patients. In addition, whole-exome sequencing was performed, followed by Sanger sequencing for verification. The first patient, a 2-year-old boy, was found to be homozygous for the previously reported c.1880C > T (p.Ala627Val) mutation. He presented with a phenotype including severe progressive cortical atrophy, moderate cerebellar atrophy, epilepsy, and microcephaly, very similar to the previously reported cases. The second case, a 9-year-old boy, carried a novel homozygous c.679T > G (p.Phe227Val) variant and presented with mild cortical atrophy, severe cerebellar atrophy, and neither clinically manifest epilepsy nor microcephaly, which were previously considered typical findings in PEBAS with TRAPPC12 mutations. Our findings suggest that clinical and brain imaging findings might be more variable than previously anticipated; however, a larger number of observations would benefit for broader phenotypic spectrum. [ABSTRACT FROM AUTHOR]

Neurodevelopmental disorders (NDDs) are clinically and genetically heterogenous; many such disorders are secondary to perturbation in brain development and/or function. The prevalence of NDDs is > 3%, resulting in significant sociocultural and economic challenges to society. With recent advances in family-based genomics, rare-variant analyses, and further exploration of the Clan Genomics hypothesis, there has been a logarithmic explosion in neurogenetic "disease-associated genes" molecular etiology and biology of NDDs; however, the majority of NDDs remain molecularly undiagnosed. We applied genome-wide screening technologies, including exome sequencing (ES) and whole-genome sequencing (WGS), to identify the molecular etiology of 234 newly enrolled subjects and 20 previously unsolved Turkish NDD families. In 176 of the 234 studied families (75.2%), a plausible and genetically parsimonious molecular etiology was identified. Out of 176 solved families, deleterious variants were identified in 218 distinct genes, further documenting the enormous genetic heterogeneity and diverse perturbations in human biology underlying NDDs. We propose 86 candidate disease-trait-associated genes for an NDD phenotype. Importantly, on the basis of objective and internally established variant prioritization criteria, we identified 51 families (51/176 = 28.9%) with multilocus pathogenic variation (MPV), mostly driven by runs of homozygosity (ROHs) – reflecting genomic segments/haplotypes that are identical-by-descent. Furthermore, with the use of additional bioinformatic tools and expansion of ES to additional family members, we established a molecular diagnosis in 5 out of 20 families (25%) who remained undiagnosed in our previously studied NDD cohort emanating from Turkey. [ABSTRACT FROM AUTHOR]

Cornelia de Lange syndrome (CdLS) is a genetically heterogeneous disorder that presents with extensive phenotypic variability, including facial dysmorphism, developmental delay/intellectual disability (DD/ID), abnormal extremities, and hirsutism. About 65% of patients harbor mutations in genes that encode subunits or regulators of thecohesin complex, including NIPBL, SMCIA, SMC3, RAD21, and HD ACS. Wiedemann-Steiner syndrome (WDSTS), which shares CdLS phenotypic features, is caused by mutations in lysine-specific methyltransferase 2A [KMT2A). Here, we performed whole-exome sequencing (WES) of 2 male siblings clinically diagnosed with WDSTS; this revealed a hemizygous, missense mutation in SMC1A that was predicted to be deleterious. Extensive clinical evaluation and WES of 32 Turkish patients clinically diagnosed with CdLS revealed the presence of a de novo heterozygous nonsense KMT2A mutation in 1 patient without characteristic WDSTS features. We also identified de novo heterozygous mutations in SMC3 or SMC1A that affected RNA splicing in 2 independent patients with combined CdLS and WDSTS features. Furthermore, in families from 2 separate world populations segregating an autosomal-recessive disorder with CdLS-like features, we identified homozygous mutations in TAF6, which encodes a core transcriptional regulatory pathway component. Together, our data, along with recent transcriptome studies, suggest that CdLS and related phenotypes may be "transcriptomopathies" ratherthan cohesinopathies. [ABSTRACT FROM AUTHOR]