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FINCA syndrome [MIM: 618278] is an autosomal recessive multisystem disorder characterized by fibrosis, neurodegeneration and cerebral angiomatosis. To date, 13 patients from nine families with biallelic NHLRC2 variants have been published. In all of them, the recurrent missense variant p.(Asp148Tyr) was detected on at least one allele. Common manifestations included lung or muscle fibrosis, respiratory distress, developmental delay, neuromuscular symptoms and seizures often followed by early death due to rapid disease progression.Here, we present 15 individuals from 12 families with an overlapping phenotype associated with nine novel NHLRC2 variants identified by exome analysis. All patients described here presented with moderate to severe global developmental delay and variable disease progression. Seizures, truncal hypotonia and movement disorders were frequently observed. Notably, we also present the first eight cases in which the recurrent p.(Asp148Tyr) variant was not detected in either homozygous or compound heterozygous state.We cloned and expressed all novel and most previously published non-truncating variants in HEK293-cells. From the results of these functional studies, we propose a potential genotype-phenotype correlation, with a greater reduction in protein expression being associated with a more severe phenotype.Taken together, our findings broaden the known phenotypic and molecular spectrum and emphasize that NHLRC2-related disease should be considered in patients presenting with intellectual disability, movement disorders, neuroregression and epilepsy with or without pulmonary involvement.

Purpose:The heavy chain of the CD98 protein (CD98hc) is encoded by the SLC3A2 gene. Together with the light subunit LAT1, CD98hc constitutes a heterodimeric transmembrane amino acid transporter. High SLC3A2 mRNA expression levels are associated with poor prognosis in patients with head and neck squamous cell carcinoma (HNSCC) treated with radiochemotherapy. Little is known regarding the CD98hc protein–mediated molecular mechanisms of tumor radioresistance.Experimental Design:CD98hc protein expression levels were correlated with corresponding tumor control dose 50 (TCD50) in HNSCC xenograft models. Expression levels of CD98hc and LAT1 in HNSCC cells were modulated by siRNA or CRISPR/Cas9 gene editing. HNSCC cell phenotypes were characterized by transcription profiling, plasma membrane proteomics, metabolic analysis, and signaling pathway activation. Expression levels of CD98hc and LAT1 proteins were examined by IHC analysis of tumor tissues from patients with locally advanced HNSCC treated with primary radiochemotherapy (RCTx). Primary endpoint was locoregional tumor control (LRC).Results:High expression levels of CD98hc resulted in an increase in mTOR pathway activation, amino acid metabolism, and DNA repair as well as downregulation of oxidative stress and autophagy. High expression levels of CD98hc and LAT1 proteins were significantly correlated and associated with an increase in radioresistance in HNSCC in vitro and in vivo models. High expression of both proteins identified a poor prognosis subgroup in patients with locally advanced HNSCC after RCTx.Conclusions:We found that CD98hc-associated signaling mechanisms play a central role in the regulation of HNSCC radioresistance and may be a promising target for tumor radiosensitization.

Supplementary discussion; Supplementary methods; Supplementary tables S1-S8; Supplementary figures S1-S8.

Sleep apnea is a common disorder that represents a global public health burden. KCNK3 encodes TASK-1, a K+ channel implicated in the control of breathing, but its link with sleep apnea remains poorly understood. Here we describe a new developmental disorder with associated sleep apnea (developmental delay with sleep apnea, or DDSA) caused by rare de novo gain-of-function mutations in KCNK3. The mutations cluster around the ‘X-gate’, a gating motif that controls channel opening, and produce overactive channels that no longer respond to inhibition by G-protein-coupled receptor pathways. However, despite their defective X-gating, these mutant channels can still be inhibited by a range of known TASK channel inhibitors. These results not only highlight an important new role for TASK-1 K+ channels and their link with sleep apnea but also identify possible therapeutic strategies.

FINCA syndrome is an autosomal recessive inherited multisystemic disorder characterized by pulmonary fibrosis, neurodegeneration and cerebral angiomatosis. So far, 13 patients from nine families with biallelic NHLRC2 variants have been published. In all of them, the recurrent missense variant p.(Asp148Tyr) was detected at least on one allele. Common manifestations comprised pulmonary fibrosis, respiratory distress, developmental delay, muscular hypotonia, dystonia, seizures and brain atrophy, followed mostly by early demise due to progression of disease. Here, we present ten individuals from eight families with an overlapping but static phenotype with much longer survival, associated with seven novel NHLRC2 variants identified by exome analysis. All of the here described patients presented with severe global developmental delay. While seizures and EEG abnormalities were observed as frequent manifestations, eight individuals did not show any signs of pulmonary involvement or distinct MRI abnormalities. Notably, we also present the first seven cases in which the recurrent p.(Asp148Tyr) variant was not detected, neither in homozygous nor in compound heterozygous state. Interestingly, none of these cases presented with the classic FINCA phenotype. However, bioinformatic modeling and analyses could not establish a distinct genotype phenotype correlation. Taken together, our findings broaden the known phenotypic and molecular spectrum and propose that NHLRC2 related disease should also be considered in patients presenting with intellectual disability, movement disorders, neuroregression and epilepsy without pulmonary findings.

Cyclin D2 (CCND2) is a critical cell cycle regulator and key member of the cyclin D2-CDK4 (DC) complex. De novo variants of CCND2 clustering in the distal part of the protein have been identified as pathogenic causes of brain overgrowth (megalencephaly, MEG) and severe cortical malformations in children including the megalencephaly-polymicrogyria-polydactyly-hydrocephalus (MPPH) syndrome. Megalencephaly-associated CCND2 variants are localized to the terminal exon and result in accumulation of degradation-resistant protein. We identified five individuals from three unrelated families with novel variants in the proximal region of CCND2 associated with microcephaly, mildly simplified cortical gyral pattern, symmetric short stature, and mild developmental delay. Identified variants include de novo frameshift variants and a dominantly inherited stop-gain variant segregating with the phenotype. This is the first reported association between proximal CCND2 variants and microcephaly, to our knowledge. This series expands the phenotypic spectrum of CCND2-related disorders and suggests that distinct classes of CCND2 variants are associated with reciprocal effects on human brain growth (microcephaly and megalencephaly due to possible loss or gain of protein function, respectively), adding to the growing paradigm of inverse phenotypes due to dysregulation of key brain growth genes.

Sleep apnea is a common disorder that represents a global public health burden.KCNK3encodes TASK-1, a K+channel implicated in the control of breathing, but its link with sleep apnea remains poorly understood. Here we describe a novel developmental disorder with sleep apnea caused by rarede novogain-of-function mutations inKCNK3. The mutations cluster around the ‘X-gate’, a gating motif which controls channel opening, and produce overactive channels that no longer respond to inhibition by G-protein coupled receptor pathways, but which can be inhibited by several clinically relevant drugs. These findings demonstrate a clear role for TASK-1 in sleep apnea and identify possible therapeutic strategies.

The DEAD/DEAH box RNA helicases are a superfamily of proteins involved in the processing and transportation of RNA within the cell. A growing literature supports this family of proteins as contributing to various types of human disorders from neurodevelopmental disorders to syndromes with multiple congenital anomalies. This article presents a cohort of nine unrelated individuals with de novo missense alterations in DDX23 (Dead-Box Helicase 23). The gene is ubiquitously expressed and functions in RNA splicing, maintenance of genome stability, and the sensing of double-stranded RNA. Our cohort of patients, gathered through GeneMatcher, exhibited features including tone abnormalities, global developmental delay, facial dysmorphism, autism spectrum disorder, and seizures. Additionally, there were a variety of other findings in the skeletal, renal, ocular, and cardiac systems. The missense alterations all occurred within a highly conserved RecA-like domain of the protein, and are located within or proximal to the DEAD box sequence. The individuals presented in this article provide evidence of a syndrome related to alterations in DDX23 characterized predominantly by atypical neurodevelopment.

[This corrects the article DOI: 10.1371/journal.pone.0201041.].

Pierpont syndrome (OMIM #602342) is a rare disorder characterized by developmental delay, characteristic facial gestalt, hearing loss, and abnormal fat distribution in the distal limbs. A specific mutation in TBL1XR1 [c.1337A>G; p.(Tyr446Cys)] has been described recently in six unrelated patients with Pierpont syndrome. We report on a male child with developmental delay, distinctive facial dysmorphic features, dystrophy, and abnormal fat distribution in the feet, in whom we identified the identical TBL1XR1 mutation. This patient also had additional clinical features including microphthalmia, pendular nystagmus, cryptorchidism, dermal sinus, and peripheral joint laxity, which had not been reported previously in association with Pierpont syndrome. This patient corroborates the assumption that Pierpont syndrome is exclusively caused by the specific TBL1XR1 missense mutation p.(Tyr446Cys) and the additional features broaden the phenotypic spectrum of this rare disorder.

Posterior amorphous corneal dystrophy (PACD) (OMIM 612868) is a rare autosomal dominant disorder characterized by partial or complete posterior lamellar corneal opacification, decreased corneal thickness and flattening of the corneal curvature. PACD is associated with heterozygous deletions in chromosome band 12q21.33 harboring DCN, KERA, LUM, and EPYC which encode small leucine-rich proteoglycans.We report on a 7-year-old male patient with PACD who had an interstitial deletion of 1.3 Mb in 12q21.33. His mother carried a balanced insertional translocation involving this 12q21.33 segment which was inserted into the proximal part of the long arm of one chromosome 13.The patient corroborates previous observations that PACD is a contiguous gene syndrome caused by combined haploinsufficiency of DCN, KERA, LUM, and EPYC and provides the first example of a balanced chromosome rearrangement involving 12q21.33 in an unaffected parent.

Purpose: The heavy chain of the CD98 protein (CD98hc) is encoded by the SLC3A2 gene. Together with the light subunit LAT1, CD98hc constitutes a heterodimeric transmembrane amino acid transporter. High SLC3A2 mRNA expression levels are associated with poor prognosis in patients with head and neck squamous cell carcinoma (HNSCC) treated with radiochemotherapy. Little is known regarding the CD98hc protein–mediated molecular mechanisms of tumor radioresistance. Experimental Design: CD98hc protein expression levels were correlated with corresponding tumor control dose 50 (TCD50) in HNSCC xenograft models. Expression levels of CD98hc and LAT1 in HNSCC cells were modulated by siRNA or CRISPR/Cas9 gene editing. HNSCC cell phenotypes were characterized by transcription profiling, plasma membrane proteomics, metabolic analysis, and signaling pathway activation. Expression levels of CD98hc and LAT1 proteins were examined by IHC analysis of tumor tissues from patients with locally advanced HNSCC treated with primary radiochemotherapy (RCTx). Primary endpoint was locoregional tumor control (LRC). Results: High expression levels of CD98hc resulted in an increase in mTOR pathway activation, amino acid metabolism, and DNA repair as well as downregulation of oxidative stress and autophagy. High expression levels of CD98hc and LAT1 proteins were significantly correlated and associated with an increase in radioresistance in HNSCC in vitro and in vivo models. High expression of both proteins identified a poor prognosis subgroup in patients with locally advanced HNSCC after RCTx. Conclusions: We found that CD98hc-associated signaling mechanisms play a central role in the regulation of HNSCC radioresistance and may be a promising target for tumor radiosensitization.

Truncating mutations in the last and penultimate exons of the PPM1D gene were recently described as a cause for mild to severe intellectual disability in fourteen patients. Feeding difficulties, periods of fever and vomiting as well as a high pain threshold were described as additional characteristic features and the disorder was subsequently termed "intellectual developmental disorder with gastrointestinal difficulties and high pain threshold (IDDGIP)" in the OMIM database (MIM # 617450). Here we report on an additional patient carrying a novel de novo truncating mutation NM_003620.3: c.1535del, p.(Asn512Ilefs*2) in the last exon of PPM1D. While the patient showed features overlapping with the reported phenotype, such as a short stature and small hands and feet, he also presented with additional features like cleft lip and palate and an aberrant right subclavian artery. Notably, the patient did not have any gastrointestinal difficulties or periods of fever, indicating variability of the phenotype of patients with PPM1D mutations.

Phosphoribosylpyrophosphate synthetase (PRPPS) superactivity (OMIM 300661) is a rare inborn error of purine metabolism that is caused by gain-of-function mutations in the X-chromosomal gene PRPS1 (Xq22.3). Clinical characteristics include congenital hyperuricemia and hyperuricosuria, gouty arthritis, urolithiasis, developmental delay, hypotonia, recurrent infections, short stature, and hearing loss. Only eight families with PRPPS superactivity and PRPS1 gain-of-function mutations have been reported to date. We report on a 7-year-old boy with congenital hyperuricemia, urolithiasis, developmental delay, short stature, hypospadias, and facial dysmorphisms. His mother also suffered from hyperuricemia that was diagnosed at age 13 years. A novel PRPS1 missense mutation (c.573G>C, p.[Leu191Phe]) was detected in the proband and his mother. Enzyme activity analysis confirmed superactivity of PRPP synthetase. Analysis of the crystal structure of human PRPPS suggests that the Leu191Phe mutation affects the architecture of both allosteric sites, thereby preventing the allosteric inhibition of the enzyme. The family reported here broadens the clinical spectrum of PRPPS superactivity and indicates that this rare metabolic disorder might be associated with a recognizable facial gestalt.

Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer death in western countries, although lifetime risk is estimated at only 1.3% in the general population. BRCA2 mutations, however, have been attributed with a lifetime risk for PDAC development of 5-10%, while the risk for PDAC development in BRCA1 mutation carriers has been the subject of an ongoing scientific discussion, with current estimates of an increased PDAC risk of only 2-4-fold. We retrospectively analyzed 180 pedigrees for occurrence of PDAC. All families were counselled for hereditary breast and ovarian cancer (HBOC) within three years (2015 to 2017) at the Center for Hereditary Breast and Ovarian Cancer in Dresden. The pedigrees of 111 families with a pathogenic BRCA1 germline mutation and of 69 families with a pathogenic BRCA2 germline mutation were available for analysis. Whenever possible genetic testing (NGS or targeted sequencing) was performed using blood and/or tumor tissue of affected individuals. 14 “BRCA1 families” were identified to have at least one family member affected by PDAC (12.6% of families). Three of the patients were available for testing and carrier status could be confirmed in all of them. According to formal genetic risk calculation 6 of the PDAC patients had a mutation carrier risk of 50%, 5 of 25% and 1 of 12.5%. Age of onset (AO) of the disease was known in 13 of the families and the mean AO, calculated for these patients, was 58.7 years. Interestingly, two female Mutation carriers had both breast- and pancreatic cancer and one family with a BRCA1 mutation presented with two sisters with PDAC. Tumor tissue was available from one of them and sequencing indicated loss-of-heterozygosity, supporting the assumption that the BRCA1 mutation might have been causative for tumorigenesis. Of the “BRCA2 families” 10 (14,5%) were identified to have one family member each with PDAC. To date, however, none of them was available for genetic testing. 3 of the patients had a mutation carrier risk calculated at 50%, 5 at 25%, 1 at 12.5% and 1 at 6.25%. The mean AO was calculated to be 60.1 years. One female PDAC patient additionally had breast cancer and one of the male patients also suffered from prostate cancer. While the number of families represented in this retrospective study is limited, our observations indicate that BRCA1 mutations might be underdiagnosed in PDAC, especially in patients with an earlier AO. Extensive genetic analyses of PDAC patients will be necessary in order to elucidate this presumption and could also indicate whether additional genetic risk modifiers play a role in PAC development in BRCA1/2 families. Citation Format: Evelin Schrock, Karl Hackmann, Franziska Kuhlee, Arne Jahn, Johannes Wagner, Anne-Karin Kahlert, Joseph Porrmann, Andreas Tzschach, Daniela Aust, Gustavo Baretton, Karin Kast, Pauline Wimberger, Michael Laniado, Christoph Kahlert, Thilo Welsch, Jürgen Weitz, Barbara Klink, Andreas Rump, Laura Gieldon. Pedigree analysis equally identifies cases of pancreatic cancer in families with BRCA1 and BRCA2 mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1410.

The MASTER (Molecularly Aided Stratification for Tumor Eradication Research) Program of the NCT (National Center for Tumor Diseases) Heidelberg and the DKTK (German Cancer Consortium) is situated at the interface of cancer genomics and clinical oncology to provide whole exome/genome and transcriptome sequencing to selected patients with unmet medical need, and to evaluate the utility of such an approach regarding molecular stratification and individualized, biology-guided treatment. The program has enabled implementation of a shared, DKTK-wide workflow for rapid-turnaround clinical sequencing, comprising all steps from sample processing to reporting of results by a dedicated molecular tumor board. In clinical cancer genome sequencing programs, bioinformatics pipelines normally exclude germline variants detected in matched normal tissues to select for somatic mutations. However, in younger cancer patients (less than 51 years of age) and/or patients with rare cancer entities, which are eligible for analysis within MASTER, we anticipated an enrichment of patients with a possible hereditary background. If germline variants would be excluded in such cases a priori, relevant pathogenic mutations responsible for cancer development might be missed. Importantly, such mutations could also be therapeutically relevant. This applies in particular to tumors with mutations in genes involved in DNA damage response signaling, e.g. BRCA1/2, PALB2, ATM, and others, which respond to treatment with PARP inhibitors and platinum-based chemotherapy. Furthermore, germline mutations in these genes are responsible for hereditary breast and ovarian cancer and more than 120 tumor predisposition syndromes (TPS) known to date. Therefore analysis of germline variants of all known hereditary cancer genes was included as part of the NCT/DKTK MASTER workflow since 2015. A board-certified clinical geneticists experienced in evaluating rare private germline variants performed data interpretation. Recommendations were provided to the clinical oncologists for referral of patients to a TPS center for genetic counseling, further diagnostics, surveillance, and tumor prevention measures. We here present results from 321 NCT/DKTK MASTER patients analyzed thus far. Previously unknown pathogenic germline variants in 22 different tumor susceptibility genes, such as BRCA1/2, PALB2, ATM, NF1, MEN1, RB1, APC, SDHB, CDH1, and others, were detected in 36 patients (11%) with various cancers. We thus demonstrate the importance of evaluating germline variants obtained by “omics”-based molecular diagnostic approaches under clinical conditions. Furthermore, our results not only had implications for further surveillance of patients and their families, but also contributed to clinically “actionable” treatment recommendations. Citation Format: Evelin Schrock, Barbara Hutter, Martina Fröhlich, Falk Zakrzewski, Sebastian Uhrig, Andreas Rump, Karl Hackmann, Joseph Porrmann, Laura Gieldon, Daniela Richter, Albrecht Stenzinger, Thomas Kindler, Wilko Weichert, Philipp J. Jost, Christian Brandts, Klaus Schulze-Osthoff, Johanna Falkenhorst, Sebastian Bauer, Frederick Klauschen, Konrad Klinghammer, Gunnar Folprecht, Martin Wermke, Karsten Spiekermann, Benedikt Brors, Stefan Gröschel, Christoph Heining, Peter Horak, Hanno Glimm, Stefan Fröhling, Barbara Klink. Identification of patients at risk for tumor predisposition syndromes based on the evaluation of sporadic cancer exome sequencing data: experiences from the NCT/DKTK MASTER program [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-287. doi:10.1158/1538-7445.AM2017-LB-287