Clinical, Neuroimaging, and Metabolic Footprint of the Neurodevelopmental Disorder Caused by Monoallelic HK1 Variants.

Background and Objectives: Hexokinase 1 (encoded by HK1) catalyzes the first step of glycolysis, the adenosine triphosphate-dependent phosphorylation of glucose to glucose-6-phosphate. Monoallelic HK1 variants causing a neurodevelopmental disorder (NDD) have been reported in 12 individuals. Methods: We investigated clinical phenotypes, brain MRIs, and the CSF of 15 previously unpublished individuals with monoallelic HK1 variants and an NDD phenotype. Results: All individuals had recurrent variants likely causing gain-of-function, representing mutational hot spots. Eight individuals (c.1370C>T) had a developmental and epileptic encephalopathy with infantile onset and virtually no development. Of the other 7 individuals (n = 6: c.1334C>T; n = 1: c.1240G>A), 3 adults showed a biphasic course of disease with a mild static encephalopathy since early childhood and an unanticipated progressive deterioration with, e.g., movement disorder, psychiatric disease, and stroke-like episodes, epilepsy, starting in adulthood. Individuals who clinically presented in the first months of life had (near)-normal initial neuroimaging and severe cerebral atrophy during follow-up. In older children and adults, we noted progressive involvement of basal ganglia including Leigh-like MRI patterns and cerebellar atrophy, with remarkable intraindividual variability. The CSF glucose and the CSF/blood glucose ratio were below the 5th percentile of normal in almost all CSF samples, while blood glucose was unremarkable. This biomarker profile resembles glucose transporter type 1 deficiency syndrome; however, in HK1-related NDD, CSF lactate was significantly increased in all patients resulting in a substantially different biomarker profile. Discussion: Genotype-phenotype correlations appear to exist for HK1 variants and can aid in counseling. A CSF biomarker profile with low glucose, low CSF/blood glucose, and high CSF lactate may point toward monoallelic HK1 variants causing an NDD. This can help in variant interpretation and may aid in understanding the pathomechanism. We hypothesize that progressive intoxication and/or ongoing energy deficiency lead to the clinical phenotypes and progressive neuroimaging findings.

Expanded spectrum of exon 33 and 34 mutations in SRCAP and follow-up in patients with Floating-Harbor syndrome.

BACKGROUND: Floating-Harbor syndrome is a rare autosomal dominant short stature syndrome with retarded speech development, intellectual disability and dysmorphic facial features. Recently dominant mutations almost exclusively located in exon 34 of the Snf2-related CREBBP activator protein gene were identified to cause FHS. METHODS: Here we report the genetic analysis of 5 patients fulfilling the diagnostic criteria of FHS obtained by Sanger sequencing. All of them presented with short stature, speech delay as well as psychomotor delay and typical facial dysmorphism. Three patients showed a good response to growth hormone treatment. RESULTS: Two patients demonstrate novel, heterozygous de novo frameshift mutations in exon 34 (c.7396delA and c.7218dupT) leading to premature stop mutations in SRCAP (p.Val2466Tyrfs*9 and p.Gln2407Serfs*36, respectively). In two further patients we found already known SRCAP mutations in exon 34, c.7330C > T and c.7303C > T, respectively, which also lead to premature stop codons: p.Arg2444* and p.Arg2435*. In one patient, we identified a novel de novo stop mutation in exon 33 (c.6985C > T, p.Arg2329*) demonstrating that not all FHS cases are caused by mutations in exon 34 of SRCAP. CONCLUSIONS: Our data confirm a mutational hot spot in the final exon of SRCAP in the majority of FHS patients but also show that exon 33 of this gene can be affected.

Association of death receptor 4 variant (683A > C) with ovarian cancer risk in BRCA1 mutation carriers.

Dysregulation of apoptosis plays an important role in carcinogenesis. Therefore, apoptosis-associated genes like the death receptor 4 (DR4, TRAIL-R1) are interesting candidates for modifying the penetrance of breast and ovarian cancer in carriers of BRCA1 and BRCA2 mutations. The DR-4 haplotype 626C-683C [626C > G, Thr209Arg (rs4871857) and 683A > C, Glu228Ala (rs17088993)] has recently been linked to an increased risk of breast cancer. To evaluate whether DR4 626C > G or DR4 683A > C modifies the risk of breast or ovarian cancer in carriers of BRCA1 and BRCA2 mutations, we undertook a national multicenter study including data of 840 carriers of breast cancer gene (BRCA) mutations. DNA samples were collected from 12 German research centers between 1996 and 2005 and were genotyped by the Taqman allelic discrimination assay. The association between genotypes and incidence of breast or ovarian cancer data was evaluated using a Cox proportional hazards regression model. We found evidence for a significant association of DR4 683A > C with a higher risk for ovarian cancer in carriers of BRCA1 mutations [n = 557, hazard ratio 1.78 (1.24-2.55), p = 0.009]. Our results thus indicate that the DR4 683A > C variant modifies the risk of ovarian cancer in carriers of BRCA1 mutations.

New mutations of EXT1 and EXT2 genes in German patients with Multiple Osteochondromas.

Mutations in either the EXT1 or EXT2 genes lead to Multiple Osteochondromas (MO), an autosomal dominantly inherited disorder. This is a report on clinical findings and results of molecular analyses of both genes in 23 German patients affected by MO. Mutation screening was performed by using denaturing high performance liquid chromatography (dHPLC) and automated sequencing. In 17 of 23 patients novel pathogenic mutations have been identified; eleven in the EXT1 and six in the EXT2 gene. Five patients were carriers of recurrent mutations in the EXT2 gene (p.Asp227Asn, p.Gln172X, p.Gln258X) and one patient had no detectable mutation. To demonstrate their pathogenic effect on transcription, two complex mutations in EXT1 and EXT2 and three splice site mutations were characterized by mRNA investigations. The results obtained provide evidence for different aberrant splice effects - usage of new cryptic splice sites and exon skipping. Our study extends the mutational spectrum and understanding of pathogenic effects of mutations in EXT1 and EXT2.

Different phenotypes including gynecological cancer in three female patients with Peutz-Jeghers syndrome and mutations in the STK11 gene.

BACKGROUND: Peutz-Jeghers syndrome (PJS), a rare hereditary disorder, is characterized by the occurrence of gastrointestinal hamartomatous polyps associated with mucocutaneous pigmentation. Patients are at an increased cancer risk not only for gastrointestinal but also for extraintestinal neoplasms. PATIENTS AND RESULTS: We report on the clinical and molecular findings in 3 young female patients with PJS; 2 of them suffered from severe gynecological cancer. One patient died at the age of 29 years of an incurable mucin-producing cervical adenocarcinoma. Another patient had a papillary serous carcinoma of the ovary. In all patients, we identified corresponding mutations in the STK11 gene, 2 of them novel. CONCLUSION: PJS should be considered in differential diagnosis in young women with gynecological malignancies. Identification of STK11 mutations in patients and their relatives can help to improve the clinical management.

Acute myelomonocytic leukemia in a boy with LEOPARD syndrome (PTPN11 gene mutation positive).

The LEOPARD syndrome is a complex of multisystemic congenital abnormalities characterized by lentiginosis, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonary stenosis, abnormalities of genitalia, retardation of growth, and deafness (sensorineural). Mutations in PTPN11, a gene encoding the protein tyrosine phosphatase SHP-2 located on chromosome 12q24.1, have been identified in 88% of patients with LEOPARD syndrome. A missense mutation (836-->G; Tyr279Cys) in exon 7 of PTPN11 gene was identified in this patient and his mother with LEOPARD syndrome. This mutation is one of the two recurrent mutations most often associated with the syndrome. Leukemia has not previously been reported in patients with LEOPARD syndrome. The authors describe a 13-year-old boy diagnosed with both LEOPARD syndrome and acute myelomonocytic leukemia (AML-M4).

MYH Gene Status in Polish FAP Patients without APC Gene Mutations.

Familial Adenomatous Polyposis (FAP) is an inheritable predisposition for the occurrence of numerous polyps in the large intestine. In about 50% of all patients, the occurrence of the disease is conditioned by heterozygotic mutations of the APC gene. Screening for genetic factors in persons without mutations in the APC gene led to the identification of homozygotic mutations of the MYH gene as the cause of the appearance of the polyposis form which is characterized by recessive heritability and a milder course than in the case of the classic form of the disease. The authors examined 90 persons from the DNA bank of patients with FAP from the Institute of Human Genetics of the Polish Academy of Sciences in Poznan in whom no mutations in the APC gene were detected. Two of the most frequent mutations of the MYH gene (Y165C and G382D) were found to be heterozygous in 13% of patients and no other mutations in this gene coding sequence were observed. In the group with heterozygotic occurrence of the mutation in the MYH gene, the disease phenotype was not milder in comparison with the entire examined group and the mean age of the disease manifestation was even lower. This observation allows one to conclude that the employed methods of mutation screening were correct and, in the case of the examined group, the mutation ratio of the MYH gene does not precondition the occurrence of the disease, but it cannot be excluded that it may modify its phenotype. The obtained results indicate that the criteria applied during the process of FAP qualification are more rigorous than those applied in other countries.