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PURPOSE: Biallelic PIGN variants have been described in Fryns syndrome, multiple congenital anomalies-hypotonia-seizure syndrome (MCAHS), and neurologic phenotypes. The full spectrum of clinical manifestations in relation to the genotypes is yet to be reported.METHODS: Genotype and phenotype data were collated and analyzed for 61 biallelic PIGN cases: 21 new and 40 previously published cases. Functional analysis was performed for 2 recurrent variants (c.2679C>G p.Ser893Arg and c.932T>G p.Leu311Trp).RESULTS: Biallelic-truncating variants were detected in 16 patients-10 with Fryns syndrome, 1 with MCAHS1, 2 with Fryns syndrome/MCAHS1, and 3 with neurologic phenotype. There was an increased risk of prenatal or neonatal death within this group (6 deaths were in utero or within 2 months of life; 6 pregnancies were terminated). Incidence of polyhydramnios, congenital anomalies (eg, diaphragmatic hernia), and dysmorphism was significantly increased. Biallelic missense or mixed genotype were reported in the remaining 45 cases-32 showed a neurologic phenotype and 12 had MCAHS1. No cases of diaphragmatic hernia or abdominal wall defects were seen in this group except patient 1 in which we found the missense variant p.Ser893Arg to result in functionally null alleles, suggesting the possibility of an undescribed functionally important region in the final exon. For all genotypes, there was complete penetrance for developmental delay and near-complete penetrance for seizures and hypotonia in patients surviving the neonatal period.CONCLUSION: We have expanded the described spectrum of phenotypes and natural history associated with biallelic PIGN variants. Our study shows that biallelic-truncating variants usually result in the more severe Fryns syndrome phenotype, but neurologic problems, such as developmental delay, seizures, and hypotonia, present across all genotypes. Functional analysis should be considered when the genotypes do not correlate with the predicted phenotype because there may be other functionally important regions in PIGN that are yet to be discovered.

An Xq22.2 region upstream of PLP1 has been proposed to underly a neurological disease trait when deleted in 46,XX females. Deletion mapping revealed that heterozygous deletions encompassing the smallest region of overlap (SRO) spanning six Xq22.2 genes (BEX3, RAB40A, TCEAL4, TCEAL3, TCEAL1, and MORF4L2) associate with an early-onset neurological disease trait (EONDT) consisting of hypotonia, intellectual disability, neurobehavioral abnormalities, and dysmorphic facial features. None of the genes within the SRO have been associated with monogenic disease in OMIM. Through local and international collaborations facilitated by GeneMatcher and Matchmaker Exchange, we have identified and herein report seven de novo variants involving TCEAL1 in seven unrelated families: three hemizygous truncating alleles; one hemizygous missense allele; one heterozygous TCEAL1 full gene deletion; one heterozygous contiguous deletion of TCEAL1, TCEAL3, and TCEAL4; and one heterozygous frameshift variant allele. Variants were identified through exome or genome sequencing with trio analysis or through chromosomal microarray. Comparison with previously reported Xq22 deletions encompassing TCEAL1 identified a more-defined syndrome consisting of hypotonia, abnormal gait, developmental delay/intellectual disability especially affecting expressive language, autistic-like behavior, and mildly dysmorphic facial features. Additional features include strabismus, refractive errors, variable nystagmus, gastroesophageal reflux, constipation, dysmotility, recurrent infections, seizures, and structural brain anomalies. An additional maternally inherited hemizygous missense allele of uncertain significance was identified in a male with hypertonia and spasticity without syndromic features. These data provide evidence that TCEAL1 loss of function causes a neurological rare disease trait involving significant neurological impairment with features overlapping the EONDT phenotype in females with the Xq22 deletion.

Purpose High myopia (HM) is an eye disorder with both environmental and genetic factors involved. Many genetic factors responsible for HM were recognized worldwide, but little is known about genetic variants underlying HM in Central Europe. Thus, the aim of this study was to identify rare sequence variants involved in HM in families from Central Europe to better understand the genetic basis of HM. Materials and methods We assessed 17 individuals from 7 unrelated Central European families with hereditary HM using exome sequencing (ES). Segregation of selected variants in other available family members was performed using Sanger sequencing. Results Detected 73 rare variants were selected for verification. We observed 2 missense variants, c.938C>T in SLC35E2B - encoding solute carrier family 35 member E2B, and c.1642G>C in FLRT3 - encoding fibronectin leucine rich transmembrane protein, segregating with HM in one family. Conclusions FLRT3 ​and/or ​SLC35E2B ​could represent disease candidate genes and identified sequence variants might be responsible for HM in the studied family.

Background Multiple sclerosis (MS) is a common inflammatory demyelinating disease of the central nervous system. The clinical phenotype is probably modified by interactions from genetic and environmental factors. Neurofibromatosis type 1 (NF1) is an autosomal dominant neurocutaneous disease. NF1 gene mutations lead to clinical manifestation in the peripheral and central nervous system. Coexistence of MS and NF1 is a rare condition. Objective To report the case of the patient with primary progressive MS (PPMS) and NF1. Methods A retrospective analysis of a patient who has undergone whole exome sequencing confirmed by Sanger sequencing. Results We reported a novel de novo c.6817delC deletion and rs1801052 polymorphism in NF1 gene associated with NF1 symptoms, as well as numerous polymorphisms in SPG7, SPG15, SPG39 genes responsible for benign spastic paraplegia. Conclusion Co-occurrence of PPMS and NF1 may be a consequence of genetic changes.

De novo monoallelic mutations in the GNB1 gene, encoding a β subunit of heterotrimeric G proteins, cause a newly recognized disorder with the typical clinical picture of severe developmental delay/intellectual disability, hypotonia and extrapyramidal symptoms. We describe another case of the condition with manifestations of cutaneous mastocytosis associated with a novel do novo mutation GNB1NM_001282539.1: c.230G T; p.(Gly77Val). We also present the detailed clinical and etiopathogenetic discussion on previously diagnosed patients as well as suggestions for the link of the mutation with skin disease.

Choroid plexus tumors (CPT) constitute 2%–5% of all pediatric brain tumors and include high grade choroid plexus carcinoma (CPC). About 40% of CPC patients harbor germline TP53 mutations, associated with diminished survival rates. However, the number of TP53 carriers might be underestimated due to suboptimal ability of Sanger sequencing to identify mosaicism. We describe an 18-month-old boy with ultra-rare, bilateral disseminated CPC and negative family history of cancer. Next generation sequencing (NGS) revealed constitutional mosaicism of de novo TP53 mutation, which was barely detectable by Sanger sequencing. This is the first description of a de novo TP53 mutation mosaicism in a patient with CPC. Up to now four cases of de novo TP53 mutations in CPC patients have been described but none of them were mosaic. Since TP53 mutation mosaicism may have an impact on management of patients and predisposition to other cancers, a reliable method of identification is important. Our results highlight the utility of high-throughput technologies in detection of potentially important genetic markers.

Background Glycosylphosphatidylinositol (GPI)-anchor deficiencies are a new subclass of congenital disorders of glycosylation. About 26 genes are involved in the GPI-anchor biosynthesis and remodeling pathway, of which mutations in thirteen have been reported to date as causative of a diverse spectrum of intellectual disabilities. Since the clinical phenotype of these disorders varies and the number of described individuals is limited, we present new patients with inherited GPI-anchor deficiency (IGD) caused by mutations in the PGAP2 and PIGN genes. Patients and methods The first girl presented with profound psychomotor retardation, low birth parameters, and chest deformities already existing in neonatal period. The disease course was slowly progressive with severe hypotonia, chronic fever, and respiration insufficiency at the age of 6. The second girl showed profound psychomotor retardation, marked hypotonia, and high birth weight (97 centile). Dysmorphy was mild or absent in both girls. Whole exome sequencing revealed novel variants in the genes PGAP2 (c.2T>G and c.221G>A) and PIGN (c.790G>A and c.932T>G). Impaired GPI binding were was subsequently uncovered, although the hyperactivity of alkaline phosphatase (a GPI-anchored protein) occurred only in first case. Conclusions Based on our results we can conclude that: 1. GPI-anchor biosynthesis disorders may represent a relatively frequent and overlooked metabolic defect; 2. The utility of GPI binding assessment as a screening test for this group of rare diseases requires further studies.

Solitary median maxillary central incisor syndrome (SMMCI) is a rare congenital oronasal-dental midline anomaly. The aim of this paper is a presentation of a patient with SMMCI without other visible dentofacial anomalies, with a potentially new molecular etiology consisting of a gene-gene reaction and conservative therapeutic approach to nasal obstruction. Potentially pathogenic variants in the SMO gene (p.Gly422Glu) and in P2RY13 gene (p.Trp205*) inherited from the probant's father, and in the PLD2 gene (p.Gln319fs), inherited from the mother were found. A multidisciplinary approach is necessary for the management of patients with SMMCI, including a genetic consultation with genetic tests.

POLG2 associated disorders belong to the group of mitochondrial DNA (mtDNA) diseases and present with a heterogeneous clinical spectrum, various age of onset, and disease severity. We report a 39-year old female presenting with childhood-onset and progressive neuroophthalmic manifestation with optic atrophy, mixed polyneuropathy, spinal and cerebellar ataxia and generalized chorea associated with mtDNA depletion. Whole-exome sequencing identified an ultra-rare homozygous missense mutation located at Chr17: 062474101-C > A (p.Asp433Tyr) in nuclear POLG2 gene encoding PolγB, an accessory subunits of mitochondrial polymerase γ responsible for mtDNA replication. The healthy parents and 2 sisters of the patient were heterozygous for the variant. To our best knowledge, this is the first case of homozygous variant in the POLG2 gene resulting in mitochondrial depletion syndrome in an adult patient and its clinical manifestations extend the clinical spectrum of POLG2 associated diseases.

Despite recent progress in molecular karyotyping and clinical sequencing the cause of intellectual disability in a considerable subset of individuals affected by this phenotype remains elusive. As intellectual disability is also a feature of various imprinting disorders and some monogenic forms of intellectual disability are caused by epigenetic modifiers we hypothesized that changes in DNA methylation might be associated with or even causative in some cases of intellectual disability. Therefore, we performed a DNA methylation analysis of peripheral blood samples from 82 patients with intellectual disability and additional features using the HumanMethylation450 BeadChip. The findings were compared to that of 19 normal controls. Differentially methylated loci were validated by bisulfite pyrosequencing. On a global level, we failed to detect a robust DNA methylation signature segregating individuals with intellectual disability from controls. Using an individual approach, we identified 157 regions showing individual DNA methylation changes in at least one patient. These correlated to 107 genes including genes linked to conditions associated with intellectual disability, namely COLEC11, SHANK2, GLI2 and KCNQ2, as well as imprinted genes like FAM50B and MEG3. The latter was suggestive of an undiagnosed Temple syndrome which could be confirmed by diagnostic tests. Subsequent in-depth analysis of imprinted loci revealed DNA methylation changes at additional imprinted loci, i.e. PPIEL, IGF2R, MEG8 and MCTS2/HM13, in up to five patients. Our findings indicate that imprinting disorders are rare but probably under-diagnosed in patients with intellectual disability and moreover point to DNA methylation changes as potential alternative means to identify deregulated genes involved in the pathogenesis of intellectual disability.

Majority of clear cell renal cell carcinomas (ccRCCs) are diagnosed in the advanced metastatic stage resulting in dramatic decrease of patient survival. Thereby, early detection and monitoring of the disease may improve prognosis and treatment results. Recent technological advances enable the identification of genetic events associated with ccRCC and reveal significant molecular heterogeneity of ccRCC tumors. This review summarizes recent findings in ccRCC genomics and epigenomics derived from chromosomal aberrations, DNA sequencing and methylation, mRNA, miRNA expression profiling experiments. We provide a molecular insight into ccRCC pathology and recapitulate possible clinical applications of genomic alterations as predictive and prognostic biomarkers.

Summary The amino acid substitution Arg72Pro in the TP53 protein has an impact on the biochemical and biological activity of this protein, and is associated with several types of cancers. However, the Arg72Pro polymorphism exhibits inconsistent contribution as a risk factor in various cancer types. Therefore, using PCR-RFLPs, we investigated the distribution of Arg72Pro genotypes and alleles in patients with laryngeal cancer ( n = 123) and controls ( n = 300) in Poland. We observed that patients with the Pro/Pro and Arg/Pro TP53 genotypes displayed a 1.755-fold increased risk of laryngeal cancer (95% CI = 1.149–2.680, P = 0.0099). However, we did not find a significant increase in laryngeal cancer risk for the homozygous Pro/Pro TP53 genotype OR = 2.093 (95% CI = 1.046–4.192, P = 0.0530). This result suggests that the TP53Pro variant may contribute to the risk of laryngeal cancer development in Polish patients.

Polymorphisms in the selected genes controlling carcinogen metabolism (CYP1A1, CYP2D6, CYP2E1, NAT2, GSTM1, GSTT1) considered separately or in different combinations, were investigated for an association with tobacco smoke-associated squamous cell carcinoma (SCC) of the larynx. The case–control study was performed in 289 patients with laryngeal SCC and in 316 cancer-free controls; all were Caucasian males from the same region of Poland and current tobacco smokers. The DNA samples were genotyped using PCR–RFLP and multiplex PCR. The variants’ frequencies in both groups were compared; odds ratios and their 95% confidence intervals were calculated by logistic regression analyses. The CYP1A1*1/*4, CYP2D6*4/*4, NAT2*4/*6A genotypes, as well as the CYP1A1*4, CYP2D6*4 and NAT2*4 alleles, were found at significantly higher frequencies in cases than in controls indicating their role as “risk-elevating” factors in laryngeal SCC. Combined genotypes, characterized by the presence of the “risk-elevating” variants at more than one locus, often occurred together with the null variant of the GSTM1 gene and homozygous XPD A/A (Lys751Gln, A35931C) genotype. Furthermore, we identified some “protective” variants, found more frequently in controls than in cases, i.e. the NAT2*6A/*6A and NAT2*5B/*6A genotypes. A distribution of “risk” or “protection” genotypes/alleles seems to be connected with age as an occurrence or risk genes was more frequent in the group of “young” cases (≤49 years). Accumulation of certain alleles or genotypes of the CYP1A1, NAT2, GSTM1 and XPD seems to be associated with either increased or decreased risk to develop laryngeal SCC. Therefore, polymorphisms in these genes may play a role in the laryngeal cancer etiology.

One of the most troublesome failures in head and neck tumors treatment is the incidence of multiple primary tumors (MPT). The aim of the study was to identity the genetic factors associated with the predisposition of second cancer occurrence. The polymorphisms of genes involved in carcinogen metabolic activation (CYP1A1, CYP2E1), detoxication (GSTM1, GSTT1, GSTM3, NAT2,) and DNA repair (XPD /A35931C-exon 23 and C22541A-exon 6/, XRCC1 /G28152A-exon 10 and C26304T-exon 6/, XRCC3/C18067T/) were studied by PCR-based techniques to analyze genotypes and allele distribution in 84 patients with MPT correlated with 182 subjects with a single tumor of head and neck and 143 cancer-free male volunteers recruited from healthy smokers. Out of 11 polymorphisms examined significant differences between studied groups in CYP1A1, GSTM1, NAT2 genes, but not at the CYP2E1, GSTT1, GSTM3, XPD (exon 23 and 6), XRCC1 (exon 10 and 6) and XRCC3 were established. Further, the coexistence of some genotypes/alleles associated with a higher cancer risk, so called ‘risk genotypes’ was established as an added genetic factor to MPT development. The interpretation of our data indicates that the same group of low-penetration genes is involved in the development of single and multiple primary head and neck cancer but their association with MPT is significantly stronger.

The loss of chromosome Y has often been observed in human solid tumors. This chromosome aberration has been proposed as one of genetic changes predisposing men to squamous cell carcinoma of the head and neck (SCCHN). In this study, using cytogenetic analysis and fluorescence in situ hybridization we analyzed: 16 cell lines derived from primary and recurrent SCCHN, a group of 22 samples derived from of previously analyzed primary larynx tumors and their corresponding metastases and a group of eight multiple primary tumors received from two different locations within the head and neck region of the same patients. In the majority of analyzed cell lines we found both loss of chromosome Y and SRY-probe signals (68.7% of samples) and these were nearly always found in the analyzed metaphases. The whole chromosome Y was usually lost, but in two cases we observed translocation of this chromosome to chromosomes 1, 3 and 17. Among all primary tumors, 14 (63.6%) and 15 of their metastases (68.2%) showed a loss of chromosome Y in a prevailing number of analyzed nuclei. Also, in the group of primary tumors and second primary tumors, all samples had a loss of the chromosome Y in the majority of analyzed nuclei.