Clinical, radiological and histopathological features of patients with familial pulmonary fibrosis.

BACKGROUND: In familial pulmonary fibrosis (FPF) at least two biological relatives are affected. Patients with FPF have diverse clinical features. RESEARCH QUESTION: We aimed to characterize demographic and clinical features, re-evaluate high-resolution computed tomography (HRCT) scans and histopathology of surgical lung biopsies, assess survival and investigate the suitability of risk prediction models for FPF patients. STUDY DESIGN: A retrospective cohort study. METHODS: FPF data (n = 68) were collected from the medical records of Oulu University Hospital (OUH) and Oulaskangas District Hospital between 1 Jan 2000 and 11 Jan 2023. The inclusion criterion was pulmonary fibrosis (PF) (ICD 10-code J84.X) and at least one self-reported relative with PF. Clinical information was gathered from hospital medical records. HRCT scans and histology were re-evaluated. RESULTS: Thirty-seven (54.4%) of the patients were men, and 31 (45.6%) were women. The mean ages of the women and men were 68.6 and 61.7 years, respectively (p = 0.003). Thirty-seven (54.4%) patients were nonsmokers. The most common radiological patterns were usual interstitial pneumonia (UIP) (51/75.0%), unclassifiable (8/11.8%) and nonspecific interstitial pneumonia (NSIP) (3/4.4%). Pleuroparenchymal fibroelastosis (PPFE) was observed as a single or combined pattern in 13.2% of the patients. According to the 2022 guidelines for idiopathic pulmonary fibrosis (IPF), the patients were categorized as UIP (31/45.6%), probable UIP (20/29.4%), indeterminate for UIP (7/10.3%) or alternative diagnosis (10/14.7%). The histopathological patterns were UIP (7/41.2%), probable UIP (1/5.9%), indeterminate for UIP (8/47.2%) and alternative diagnosis (1/5.9%). Rare genetic variants were found in 9 patients; these included telomerase reverse transcriptase (TERT, n = 6), telomerase RNA component (TERC, n = 2) and regulator of telomere elongation helicase 1 (RTEL1, n = 1). Half of the patients died (n = 29) or underwent lung transplantation (n = 5), with a median survival of 39.9 months. The risk prediction models composite physiology index (CPI), hazard ratio (HR) 1.07 (95.0% CI 1.04-1.10), and gender-age-physiology index (GAP) stage I predicted survival statistically significantly (p<0.001) compared to combined stages II and III. CONCLUSIONS: This study confirmed the results of earlier studies showing that FPF patients' radiological and histopathological patterns are diverse. Moreover, radiological and histological features revealed unusual patterns and their combinations.

Quantifying the Impact of Rare and Ultra-rare Coding Variation across the Phenotypic Spectrum.

There is a limited understanding about the impact of rare protein-truncating variants across multiple phenotypes. We explore the impact of this class of variants on 13 quantitative traits and 10 diseases using whole-exome sequencing data from 100,296 individuals. Protein-truncating variants in genes intolerant to this class of mutations increased risk of autism, schizophrenia, bipolar disorder, intellectual disability, and ADHD. In individuals without these disorders, there was an association with shorter height, lower education, increased hospitalization, and reduced age at enrollment. Gene sets implicated from GWASs did not show a significant protein-truncating variants burden beyond what was captured by established Mendelian genes. In conclusion, we provide a thorough investigation of the impact of rare deleterious coding variants on complex traits, suggesting widespread pleiotropic risk.

Epidemiological, clinical, and genetic characteristics of paediatric genetic white matter disorders in Northern Finland.

AIM: To examine the epidemiological, clinical, and genetic characteristics of paediatric patients with genetic white matter disorders (GWMDs) in Northern Finland. METHOD: A longitudinal population-based cohort study was conducted in the tertiary catchment area of Oulu University Hospital from 1990 to 2019. Patients were identified retrospectively by International Statistical Classification of Diseases and Related Health Problems codes in hospital records and prospectively by attending physicians. Inclusion criteria were children younger than 18 years with defined GWMDs or genetic disorders associated with white matter abnormalities (WMAs) on brain magnetic resonance imaging. RESULTS: Eighty patients (mean age [SD] at the end of the study 11y [8y 6mo], range 0-35y; 45 males, 35 females) were diagnosed with a defined GWMD. The cumulative childhood incidence was 30 per 100 000 live births. Regarding those patients with 49 distinct GWMDs, 20% had classic leukodystrophies and 80% had genetic leukoencephalopathies. The most common leukodystrophies were cerebral adrenoleukodystrophy, Krabbe disease, and Salla disease. Additionally, 29 patients (36%) had genetic aetiologies not previously associated with brain WMAs or they had recently characterised GWMDs, including SAMD9L- and NHLRC2-related neurological disorders. Aetiology was mitochondrial in 21% of patients. The most common clinical findings were motor developmental delay, intellectual disability, hypotonia, and spasticity. INTERPRETATION: The cumulative childhood incidence of childhood-onset GWMDs was higher than previously described. Comprehensive epidemiological and natural history data are needed before future clinical trials are undertaken. What this paper adds Forty-nine distinct genetic white matter disorders (GWMDs) were identified, with 20% of cases being classic leukodystrophies. The cumulative childhood incidence of GWMDs was higher than described previously. A considerable proportion (36%) of GWMDs were previously undefined or recently characterised GWMDs. Mitochondrial aetiology was more common (21%) than previously reported.

Analysis of functional variants in mitochondrial DNA of Finnish athletes.

BACKGROUND: We have previously reported on paucity of mitochondrial DNA (mtDNA) haplogroups J and K among Finnish endurance athletes. Here we aimed to further explore differences in mtDNA variants between elite endurance and sprint athletes. For this purpose, we determined the rate of functional variants and the mutational load in mtDNA of Finnish athletes (n = 141) and controls (n = 77) and determined the sequence variation in haplogroups. RESULTS: The distribution of rare and common functional variants differed between endurance athletes, sprint athletes and the controls (p = 0.04) so that rare variants occurred at a higher frequency among endurance athletes. Furthermore, the ratio between rare and common functional variants in haplogroups J and K was 0.42 of that in the remaining haplogroups (p = 0.0005). The subjects with haplogroup J and K also showed a higher mean level of nonsynonymous mutational load attributed to common variants than subjects with the other haplogroups. Interestingly, two of the rare variants detected in the sprint athletes were the disease-causing mutations m.3243A > G in MT-TL1 and m.1555A > G in MT-RNR1. CONCLUSIONS: We propose that endurance athletes harbor an excess of rare mtDNA variants that may be beneficial for oxidative phosphorylation, while sprint athletes may tolerate deleterious mtDNA variants that have detrimental effect on oxidative phosphorylation system. Some of the nonsynonymous mutations defining haplogroup J and K may produce an uncoupling effect on oxidative phosphorylation thus favoring sprint rather than endurance performance.

Correction: The genetic basis of classic nonketotic hyperglycinemia due to mutations in GLDC and AMT.

The original supplementary information included with this article contained several minor errors. Corrected Supplementary Information accompanies this corrigendum.

NHLRC2 variants identified in patients with fibrosis, neurodegeneration, and cerebral angiomatosis (FINCA): characterisation of a novel cerebropulmonary disease.

A novel multi-organ disease that is fatal in early childhood was identified in three patients from two non-consanguineous families. These children were born asymptomatic but at the age of 2 months they manifested progressive multi-organ symptoms resembling no previously known disease. The main clinical features included progressive cerebropulmonary symptoms, malabsorption, progressive growth failure, recurrent infections, chronic haemolytic anaemia and transient liver dysfunction. In the affected children, neuropathology revealed increased angiomatosis-like leptomeningeal, cortical and superficial white matter vascularisation and congestion, vacuolar degeneration and myelin loss in white matter, as well as neuronal degeneration. Interstitial fibrosis and previously undescribed granuloma-like lesions were observed in the lungs. Hepatomegaly, steatosis and collagen accumulation were detected in the liver. A whole-exome sequencing of the two unrelated families with the affected children revealed the transmission of two heterozygous variants in the NHL repeat-containing protein 2 (NHLRC2); an amino acid substitution p.Asp148Tyr and a frameshift 2-bp deletion p.Arg201GlyfsTer6. NHLRC2 is highly conserved and expressed in multiple organs and its function is unknown. It contains a thioredoxin-like domain; however, an insulin turbidity assay on human recombinant NHLRC2 showed no thioredoxin activity. In patient-derived fibroblasts, NHLRC2 levels were low, and only p.Asp148Tyr was expressed. Therefore, the allele with the frameshift deletion is likely non-functional. Development of the Nhlrc2 null mouse strain stalled before the morula stage. Morpholino knockdown of nhlrc2 in zebrafish embryos affected the integrity of cells in the midbrain region. This is the first description of a fatal, early-onset disease; we have named it FINCA disease based on the combination of pathological features that include fibrosis, neurodegeneration, and cerebral angiomatosis.

Neonatal Alexander Disease: Novel GFAP Mutation and Comparison to Previously Published Cases.

Alexander disease (AxD) is a genetic leukodystrophy caused by GFAP mutations leading to astrocyte dysfunction. Neonatal AxD is a rare phenotype with onset in the first month of life. The proband, belonging to a large pedigree with dominantly inherited benign familial neonatal epilepsy (BFNE), had a phenotype distinct from the rest of the family, with hypotonia and macrocephaly in addition to drug-resistant neonatal seizures. The patient deteriorated and passed away at 6 weeks of age. The pathological and neuroimaging data were consistent with the diagnosis of AxD. Genetic analysis of the proband identified a novel de novo GFAP missense mutation and a KCNQ2 splice site mutation segregating with the BFNE phenotype in the family. The GFAP mutation was located in the coil 2B region of GFAP protein, similar to most neonatal-onset AxD cases with an early death. The clinical and neuroradiological features of the previously published neonatal AxD patients are presented. This study further supports the classification of neonatal-onset AxD as a distinct phenotype based on the age of onset.

Breast-cancer risk in families with mutations in PALB2.

BACKGROUND: Germline loss-of-function mutations in PALB2 are known to confer a predisposition to breast cancer. However, the lifetime risk of breast cancer that is conferred by such mutations remains unknown. METHODS: We analyzed the risk of breast cancer among 362 members of 154 families who had deleterious truncating, splice, or deletion mutations in PALB2. The age-specific breast-cancer risk for mutation carriers was estimated with the use of a modified segregation-analysis approach that allowed for the effects of PALB2 genotype and residual familial aggregation. RESULTS: The risk of breast cancer for female PALB2 mutation carriers, as compared with the general population, was eight to nine times as high among those younger than 40 years of age, six to eight times as high among those 40 to 60 years of age, and five times as high among those older than 60 years of age. The estimated cumulative risk of breast cancer among female mutation carriers was 14% (95% confidence interval [CI], 9 to 20) by 50 years of age and 35% (95% CI, 26 to 46) by 70 years of age. Breast-cancer risk was also significantly influenced by birth cohort (P<0.001) and by other familial factors (P=0.04). The absolute breast-cancer risk for PALB2 female mutation carriers by 70 years of age ranged from 33% (95% CI, 25 to 44) for those with no family history of breast cancer to 58% (95% CI, 50 to 66) for those with two or more first-degree relatives with breast cancer at 50 years of age. CONCLUSIONS: Loss-of-function mutations in PALB2 are an important cause of hereditary breast cancer, with respect both to the frequency of cancer-predisposing mutations and to the risk associated with them. Our data suggest the breast-cancer risk for PALB2 mutation carriers may overlap with that for BRCA2 mutation carriers. (Funded by the European Research Council and others.).

The genetic basis of classic nonketotic hyperglycinemia due to mutations in GLDC and AMT.

PURPOSE: The study's purpose was to delineate the genetic mutations that cause classic nonketotic hyperglycinemia (NKH). METHODS: Genetic results, parental phase, ethnic origin, and gender data were collected from subjects suspected to have classic NKH. Mutations were compared with those in the existing literature and to the population frequency from the Exome Aggregation Consortium (ExAC) database. RESULTS: In 578 families, genetic analyses identified 410 unique mutations, including 246 novel mutations. 80% of subjects had mutations in GLDC. Missense mutations were noted in 52% of all GLDC alleles, most private. Missense mutations were 1.5 times as likely to be pathogenic in the carboxy terminal of GLDC than in the amino-terminal part. Intragenic copy-number variations (CNVs) in GLDC were noted in 140 subjects, with biallelic CNVs present in 39 subjects. The position and frequency of the breakpoint for CNVs correlated with intron size and presence of Alu elements. Missense mutations, most often recurring, were the most common type of disease-causing mutation in AMT. Sequencing and CNV analysis identified biallelic pathogenic mutations in 98% of subjects. Based on genotype, 15% of subjects had an attenuated phenotype. The frequency of NKH is estimated at 1:76,000. CONCLUSION: The 484 unique mutations now known in classic NKH provide a valuable overview for the development of genotype-based therapies.Genet Med 19 1, 104-111.

Novel homozygous PCK1 mutation causing cytosolic phosphoenolpyruvate carboxykinase deficiency presenting as childhood hypoglycemia, an abnormal pattern of urine metabolites and liver dysfunction.

Clinical and laboratory data were collected from three Finnish patients including a sibling pair and another unrelated child with unexplained childhood hypoglycemia. Transient elevation of alanine transaminase, lactate and tricarboxylic acid cycle intermediates, especially fumarate, were noticed in urine organic acid analysis. Exome sequencing was performed for the patients and their parents. A novel homozygous PCK1 c.925G>A (p.G309R) mutation was detected in all affected individuals. COS-1 cells transfected with mutant PCK1 transcripts were used to study the pathogenic nature of the detected variant. The COS-1 transfected cells showed the mutant gene to be incapable of producing a normally functioning cytosolic phosphoenolpyruvate carboxykinase (PEPCK) enzyme. This report further delineates the clinical phenotype of isolated cytosolic PEPCK deficiency and offers a metabolic pattern helping to recognize these patients. Cytosolic PEPCK deficiency should be considered in the differential diagnosis of children presenting with hypoglycemia, hepatic dysfunction and elevated tricarboxylic acid intermediates in urinary organic acid analysis.

A novel MTTT mutation m.15933G > A revealed in analysis of mitochondrial DNA in patients with suspected mitochondrial disease.

BACKGROUND: Mitochondrial diseases present with variable multi-organ symptoms. Common disease-causing mutations in mitochondrial DNA (mtDNA) are regularly screened in diagnostic work-up, but novel mutations may remain unnoticed. METHODS: Patients (N = 66) with a clinical suspicion of mitochondrial disease were screened for their mtDNA coding region using conformation sensitive gel electrophoresis and sequencing. Long-PCR was used to detect deletions followed by POLG1 sequencing in patients with multiple deletions. RESULTS: We discovered three novel mtDNA variants that included m.8743G > C, m.11322A > G and m.15933G > A. The novel MTTT variant m.15933G > A is suggested to be pathogenic. Analysis revealed also multiple mtDNA deletions in two patients and five nonsynonymous variants that were putatively pathogenic according to in-silico prediction algorithms. In addition, a rare haplogroup H associated m.7585_7586insT variant was discovered. CONCLUSIONS: Among patients with a suspected mitochondrial disease, a novel MTTT variant m.15933G > A was discovered and is suggested to be pathogenic. In addition, several putatively pathogenic nonsynonymous variants and rare variants were found. These findings highlight the importance of coding region mtDNA screening among patients with clinical features suggesting a mitochondrial disease, but who lack the common mitochondrial disease mutations.

Phenotype and genotype in 52 patients with Rubinstein-Taybi syndrome caused by EP300 mutations.

Rubinstein-Taybi syndrome (RSTS) is a developmental disorder characterized by a typical face and distal limbs abnormalities, intellectual disability, and a vast number of other features. Two genes are known to cause RSTS, CREBBP in 60% and EP300 in 8-10% of clinically diagnosed cases. Both paralogs act in chromatin remodeling and encode for transcriptional co-activators interacting with >400 proteins. Up to now 26 individuals with an EP300 mutation have been published. Here, we describe the phenotype and genotype of 42 unpublished RSTS patients carrying EP300 mutations and intragenic deletions and offer an update on another 10 patients. We compare the data to 308 individuals with CREBBP mutations. We demonstrate that EP300 mutations cause a phenotype that typically resembles the classical RSTS phenotype due to CREBBP mutations to a great extent, although most facial signs are less marked with the exception of a low-hanging columella. The limb anomalies are more similar to those in CREBBP mutated individuals except for angulation of thumbs and halluces which is very uncommon in EP300 mutated individuals. The intellectual disability is variable but typically less marked whereas the microcephaly is more common. All types of mutations occur but truncating mutations and small rearrangements are most common (86%). Missense mutations in the HAT domain are associated with a classical RSTS phenotype but otherwise no genotype-phenotype correlation is detected. Pre-eclampsia occurs in 12/52 mothers of EP300 mutated individuals versus in 2/59 mothers of CREBBP mutated individuals, making pregnancy with an EP300 mutated fetus the strongest known predictor for pre-eclampsia. © 2016 Wiley Periodicals, Inc.

The Quality of Genetic Counseling and Connected Factors as Evaluated by Male BRCA1/2 Mutation Carriers in Finland.

There is little written about the quality of genetic counseling for men with the BRCA1/2 mutation. The purpose of this study was to describe the quality of genetic counseling and connected factors according to Finnish male BRCA1/2 mutation carriers' (n = 35) perspectives and reasons for seeking genetic counseling. Data were collected from the Departments of Clinical Genetics at five Finnish university hospitals. The exploratory study design was conducted using a 51-item questionnaire based on a previously devised quality of counseling model and analyzed using non-parametric tests and principle content analysis. The satisfaction level with genetic counseling was high, especially with regard to the content of genetic counseling. The benefit of genetic counseling on the quality of life differed significantly (p < 0.001-0.009) from other factors. In particular, genetic counseling was in some cases associated to reduce the quality of life. Only 49 % of the male carriers felt they received sufficient counseling on social support. Attention to individual psychosocial support was proposed as an improvement to genetic counseling. Primary and secondary reasons for seeking genetic counseling and background information, such as education, affected the perceived quality of genetic counseling. The results of the study could be used to tailor genetic counseling for male BRCA1/2 mutation carriers.

Mutations in SRCAP, encoding SNF2-related CREBBP activator protein, cause Floating-Harbor syndrome.

Floating-Harbor syndrome (FHS) is a rare condition characterized by short stature, delayed osseous maturation, expressive-language deficits, and a distinctive facial appearance. Occurrence is generally sporadic, although parent-to-child transmission has been reported on occasion. Employing whole-exome sequencing, we identified heterozygous truncating mutations in SRCAP in five unrelated individuals with sporadic FHS. Sanger sequencing identified mutations in SRCAP in eight more affected persons. Mutations were de novo in all six instances in which parental DNA was available. SRCAP is an SNF2-related chromatin-remodeling factor that serves as a coactivator for CREB-binding protein (CREBBP, better known as CBP, the major cause of Rubinstein-Taybi syndrome [RTS]). Five SRCAP mutations, two of which are recurrent, were identified; all are tightly clustered within a small (111 codon) region of the final exon. These mutations are predicted to abolish three C-terminal AT-hook DNA-binding motifs while leaving the CBP-binding and ATPase domains intact. Our findings show that SRCAP mutations are the major cause of FHS and offer an explanation for the clinical overlap between FHS and RTS.

Evidence for the additivity of rare and common variant burden throughout the spectrum of intellectual disability.

Intellectual disability (ID) is a common disorder, yet there is a wide spectrum of impairment from mild to profoundly affected individuals. Mild ID is seen as the low extreme of the general distribution of intelligence, while severe ID is often seen as a monogenic disorder caused by rare, pathogenic, highly penetrant variants. To investigate the genetic factors influencing mild and severe ID, we evaluated rare and common variation in the Northern Finland Intellectual Disability cohort (n = 1096 ID patients), a cohort with a high percentage of mild ID (n = 550) and from a population bottleneck enriched in rare, damaging variation. Despite this enrichment, we found only a small percentage of ID was due to recessive Finnish-enriched variants (0.5%). A larger proportion was linked to dominant variation, with a significant burden of rare, damaging variation in both mild and severe ID. This rare variant burden was enriched in more severe ID (p = 2.4e-4), patients without a relative with ID (p = 4.76e-4), and in those with features associated with monogenic disorders. We also found a significant burden of common variants associated with decreased cognitive function, with no difference between mild and more severe ID. When we included common and rare variants in a joint model, the rare and common variants had additive effects in both mild and severe ID. A multimodel inference approach also found that common and rare variants together best explained ID status (ΔAIC = 16.8, ΔBIC = 10.2). Overall, we report evidence for the additivity of rare and common variant burden throughout the spectrum of intellectual disability.

Evaluation of the need for routine clinical testing of PALB2 c.1592delT mutation in BRCA negative Northern Finnish breast cancer families.

BACKGROUND: Testing for mutations in the BRCA1 and BRCA2 genes among high-risk breast cancer patients has become a routine practice among clinical geneticists. Unfortunately, however, the genetic background of a majority of the cases coming to the clinics remains currently unexplained, making genetic counseling rather challenging. In recent years it has become evident world-wide that also women carrying a heterozygous germline mutation in PALB2 are at significantly increased risk of getting breast cancer. We have previously studied the clinical as well as biological impact of the PALB2 c.1592delT founder mutation occurring in about 1% of Finnish breast cancer patients unselected for their family history of disease, and our results demonstrated a 40% increased breast cancer risk by age 70 for female mutation carriers. Thus, this relatively common mutation in PALB2 is associated with a high risk of developing breast cancer. The aim of the current study was to analyze whether female index individuals of breast cancer families who had tested negative for germline mutations in BRCA1/BRCA2 as part of genetic counseling services should be offered mutation testing for PALB2 c.1592delT. METHODS: The study cohort consisted of altogether 223 individuals who had contacted the Department of Clinical Genetics at the Oulu University Hospital in Finland between the years 1997 and 2011 for counseling on hereditary breast and/or ovarian cancer risk. 101 of them met our inclusion criteria. Of these, 10 persons were now deceased, but 6 of them had participated in one of our previous studies on PALB2. Seventy (77%) of the remaining 91 persons responded positively to our study invitation. Chart review of updated pedigree data led to the exclusion of 14 further individuals not meeting the selection criteria. RESULT: Of the 56 alive affected female individuals screened for PALB2 c.1592delT, altogether two (3.6%) tested positive for this mutation. In addition, of the previously tested but now deceased 6 persons eligible for the current study, one more mutation carrier was observed. Therefore, overall 4.8% (3/62) of the tested individuals belonging to the Northern Finnish 1997-2011 study cohort turned out to be carriers of the PALB2 c.1592delT allele. CONCLUSIONS: Given the potential benefits versus harms of this testing, the result of our study suggest that PALB2 c.1592delT should be a routine part of the genetic counseling protocol for Finnish high-risk breast cancer cases tested negative for mutations in BRCA1/BRCA2.

Mitochondrial DNA variant m.15218A > G in Finnish epilepsy patients who have maternal relatives with epilepsy, sensorineural hearing impairment or diabetes mellitus.

BACKGROUND: Mitochondrial diseases caused by mutations in mitochondrial DNA (mtDNA) affect tissues with high energy demand. Epilepsy is one of the manifestations of mitochondrial dysfunction when the brain is affected. We have studied here 79 Finnish patients with epilepsy and who have maternal first- or second-degree relatives with epilepsy, sensorineural hearing impairment or diabetes mellitus. METHODS: The entire mtDNA was studied by using conformation sensitive gel electrophoresis and PCR fragments that differed in mobility were directly sequenced. RESULTS: We found a common nonsynonymous variant m.15218A > G (p.T158A, MTCYB) that occurs in haplogroup U5a1 to be more frequent in patients with epilepsy. The m.15218A > G variant was present in five patients with epilepsy and in four out of 403 population controls (p = 0.0077). This variant was present in two branches in the phylogenetic network constructed on the basis of mtDNA variation among the patients. Three algorithms predicted that m.15218A > G is damaging in effect. CONCLUSIONS: We suggest that the m.15218A > G variant is mildly deleterious and that mtDNA involvement should be considered in patients with epilepsy and who have a maternal history of epilepsy, sensorineural hearing impairment or diabetes mellitus.

WFS1 variants in Finnish patients with diabetes mellitus, sensorineural hearing impairment or optic atrophy, and in suicide victims.

Mutations in the wolframin gene, WFS1, cause Wolfram syndrome, a rare recessive neurodegenerative disorder. The clinical features include early-onset bilateral optic atrophy (OA), diabetes mellitus (DM), diabetes insipidus, hearing impairment, urinary tract abnormalities and psychiatric illness, and, furthermore, WFS1 variants appear to be associated with non-syndromic DM and hearing impairment. Variation of WFS1 was investigated in Finnish subjects consisting 182 patients with DM, 117 patients with sensorineural hearing impairment (SNHI) and 44 patients with OA, and in 95 suicide victims. Twenty-two variants were found in the coding region of WFS1, including three novel nonsynonymous variants. The frequency of the p.[His456] allele was significantly higher in the patients with SNHI (11.5%; corrected P=0.00008), DM (6.6%; corrected P=0.036) or OA (9.1%; corrected P=0.043) than that in the 285 controls (3.3%). The frequency of the p.[His611] allele was 55.8% in the patients with DM being higher than that in the controls (47%; corrected P=0.039). The frequencies of p.[His456] and p.[His611] were similarly increased in an independent group of patients with DM (N=299). The results support previous findings that genetic variation of WFS1 contributes to the risk of DM and SNHI.

Clinical and Genetic Characteristics of Finnish Patients with Autosomal Recessive and Dominant Non-Syndromic Hearing Loss Due to Pathogenic TMC1 Variants.

Sensorineural hearing loss (SNHL) is one of the most common sensory deficits worldwide, and genetic factors contribute to at least 50−60% of the congenital hearing loss cases. The transmembrane channel-like protein 1 (TMC1) gene has been linked to autosomal recessive (DFNB7/11) and autosomal dominant (DFNA36) non-syndromic hearing loss, and it is a relatively common genetic cause of SNHL. Here, we report eight Finnish families with 11 affected family members with either recessively inherited homozygous or compound heterozygous TMC1 variants associated with congenital moderate-to-profound hearing loss, or a dominantly inherited heterozygous TMC1 variant associated with postlingual progressive hearing loss. We show that the TMC1 c.1534C>T, p.(Arg512*) variant is likely a founder variant that is enriched in the Finnish population. We describe a novel recessive disease-causing TMC1 c.968A>G, p.(Tyr323Cys) variant. We also show that individuals in this cohort who were diagnosed early and received timely hearing rehabilitation with hearing aids and cochlear implants (CI) have reached good speech perception in noise. Comparison of the genetic data with the outcome of CI rehabilitation increases our understanding of the extent to which underlying pathogenic gene variants explain the differences in CI rehabilitation outcomes.

Mutations in STAT3 and diagnostic guidelines for hyper-IgE syndrome.

BACKGROUND: The hyper-IgE syndrome (HIES) is a primary immunodeficiency characterized by infections of the lung and skin, elevated serum IgE, and involvement of the soft and bony tissues. Recently, HIES has been associated with heterozygous dominant-negative mutations in the signal transducer and activator of transcription 3 (STAT3) and severe reductions of T(H)17 cells. OBJECTIVE: To determine whether there is a correlation between the genotype and the phenotype of patients with HIES and to establish diagnostic criteria to distinguish between STAT3 mutated and STAT3 wild-type patients. METHODS: We collected clinical data, determined T(H)17 cell numbers, and sequenced STAT3 in 100 patients with a strong clinical suspicion of HIES and serum IgE >1000 IU/mL. We explored diagnostic criteria by using a machine-learning approach to identify which features best predict a STAT3 mutation. RESULTS: In 64 patients, we identified 31 different STAT3 mutations, 18 of which were novel. These included mutations at splice sites and outside the previously implicated DNA-binding and Src homology 2 domains. A combination of 5 clinical features predicted STAT3 mutations with 85% accuracy. T(H)17 cells were profoundly reduced in patients harboring STAT3 mutations, whereas 10 of 13 patients without mutations had low (<1%) T(H)17 cells but were distinct by markedly reduced IFN-gamma-producing CD4(+)T cells. CONCLUSION: We propose the following diagnostic guidelines for STAT3-deficient HIES. Possible: IgE >1000IU/mL plus a weighted score of clinical features >30 based on recurrent pneumonia, newborn rash, pathologic bone fractures, characteristic face, and high palate. Probable: These characteristics plus lack of T(H)17 cells or a family history for definitive HIES. Definitive: These characteristics plus a dominant-negative heterozygous mutation in STAT3.