Reduced irisin levels in patients with acromegaly.

OBJECTIVES: Several metabolic disturbances are seen in acromegaly however, data regarding the contribution of irisin to these disturbances is currently insufficient. In a cohort of patients with acromegaly, we measured serum irisin levels in active and controlled cases and determined independent factors that effect serum irisin including fibronectin type III domain-containing protein 5 (FNDC5) genotyping. METHODS: A cross-sectional case-control study including 46 patients with acromegaly (28 F/18 M, age: 50.3 ± 12.1 year, BMI: 30.7 ± 5.1 kg/m2) and 81 age-, gender-, body mass index- and body composition-matched healthy controls was conducted. 15 acromegalic patients (33%) had active disease. Irisin levels were measured by enzyme-linked immunosorbent assay. Three different regions (rs3480, rs1746661, and rs16835198) of FNDC5 were subjected to polymorphism analyses. RESULTS: Both groups were overweight and had similar body composition. Irisin levels were lower in patients with acromegaly than controls (median [IQR]: 44.8 [41.7-46.7] ng/mL vs. 51.7 [45.5-60.1] ng/mL, p≤0.001, respectively). Active and controlled patients had similar irisin levels. Irisin was not correlated with growth hormone (GH), insulin-like growth factor 1 (IGF-1), and IGF-1 index. In multiple linear regression model, somatostatin receptor ligand use (ß=-20.30, 95% CI [-34]-[-6], p=0.006) was determined as the only independent factor that affect serum irisin. CONCLUSIONS: Serum irisin levels are low in patients with acromegaly who are on somatostatin receptor ligand therapy. Single nucleotide polymorphisms (SNPs) of FNDC5 have no independent effects on circulating irisin levels under somatostatin ligand action. Endocrine muscle functions also seem to be regulated by somatostatin action, which requires further studies.

FXR1-related congenital myopathy: expansion of the clinical and genetic spectrum.

BACKGROUND: Biallelic pathogenic variants in FXR1 have recently been associated with two congenital myopathy phenotypes: a severe form associated with hypotonia, long bone fractures, respiratory insufficiency and infantile death, and a milder form characterised by proximal muscle weakness with survival into adulthood. OBJECTIVE: We report eight patients from four unrelated families with biallelic pathogenic variants in exon 15 of FXR1. METHODS: Whole exome sequencing was used to detect variants in FXR1. RESULTS: Common clinical features were noted for all patients, which included proximal myopathy, normal serum creatine kinase levels and diffuse muscle atrophy with relative preservation of the quadriceps femoris muscle on muscle imaging. Additionally, some patients with FXR1-related myopathy had respiratory involvement and required bilevel positive airway pressure support. Muscle biopsy showed multi-minicores and type I fibre predominance with internalised nuclei. CONCLUSION: FXR1-related congenital myopathy is an emerging entity that is clinically recognisable. Phenotypic variability associated with variants in FXR1 can result from differences in variant location and type and is also observed between patients homozygous for the same variant, rendering specific genotype-phenotype correlations difficult. Our work broadens the phenotypic spectrum of FXR1-related congenital myopathy.

Interaction between Dietary Fat Intake and Metabolic Genetic Risk Score on 25-Hydroxyvitamin D Concentrations in a Turkish Adult Population.

Previous studies have pointed out a link between vitamin D status and metabolic traits, however, consistent evidence has not been provided yet. This cross-sectional study has used a nutrigenetic approach to investigate the interaction between metabolic-genetic risk score (GRS) and dietary intake on serum 25-hydroxyvitamin D [25(OH)D] concentrations in 396 unrelated Turkish adults, aged 24-50 years. Serum 25(OH)D concentration was significantly lower in those with a metabolic-GRS ≥ 1 risk allele than those with a metabolic-GRS < 1 risk allele (p = 0.020). A significant interaction between metabolic-GRS and dietary fat intake (energy%) on serum 25(OH)D levels was identified (Pinteraction = 0.040). Participants carrying a metabolic-GRS ≥ 1 risk allele and consuming a high fat diet (≥38% of energy = 122.3 ± 52.51 g/day) had significantly lower serum 25(OH)D concentration (p = 0.006) in comparison to those consuming a low-fat diet (<38% of energy = 82.5 ± 37.36 g/d). In conclusion, our study suggests a novel interaction between metabolic-GRS and dietary fat intake on serum 25(OH)D level, which emphasises that following the current dietary fat intake recommendation (<35% total fat) could be important in reducing the prevalence of vitamin D deficiency in this Turkish population. Nevertheless, further larger studies are needed to verify this interaction, before implementing personalized dietary recommendations for the maintenance of optimal vitamin D status.

Investigation of Genetic Causes in a Developmental Disorder: Oculoauriculovertebral Spectrum.

OBJECTIVE: Oculoauriculovertebral spectrum (OAVS) is a genetically and clinically heterogeneous disorder that occurs due to a developmental field defect of the first and second pharyngeal arches. Even though recent whole exome sequencing studies (WES) have led to identification of several genes associated with this spectrum in a subset of individuals, complete pathogenesis of OAVS remains unsolved. In this study, molecular genetic etiology of OAVS was systematically investigated. DESIGN/SETTING/PATIENTS: A cohort of 23 Turkish patients with OAVS, referred to Hacettepe University Hospital, Department of Pediatric Genetics from 2008 to 2018, was included in this study. Minimal diagnostic criteria for OAVS were considered as unilateral microtia or hemifacial microsomia with preauricular skin tag. The cohort was clinically reevaluated for craniofacial and extracranial findings. Molecular etiology was investigated using candidate gene sequencing following copy number variant (CNV) analysis. WES was also performed for 2 of the selected patients. RESULTS: Patients in the study cohort presented similar demographic and phenotypic characteristics to previously described patients in the literature except for a higher frequency of bilaterality, cardiac findings, and intellectual disability/developmental delay. CNV analysis revealed a possible genetic etiology for 3 patients (13%). Additional WES in 1 of the 2 patients uncovered a novel heterozygous nonsense variant in Elongation factor Tu GTP-binding domain-containing 2 (EFTUD2) causing mandibulofacial dysostosis with microcephaly (MFDM), which clinically overlaps with OAVS. CONCLUSION: Detailed clinical evaluation for any patient with OAVS is recommended due to a high rate of accompanying systemic findings. We further expand the existing genetic heterogeneity of OAVS by identifying several CNVs and a phenotypically overlapping disorder, MFDM.

Specific FSTL1 polymorphism may determine the risk of cardiomyopathy in patients with acromegaly.

BACKGROUND: We have investigated the role of a cardiomyokine, follistatin-like 1 (FSTL1), and its single nucleotide polymorphism on acromegalic cardiomyopathy. METHODS: The study was performed as a cross-sectional case research in a Tertiary Referral Centre. Forty-six patients with acromegaly (29 F-17 M, mean age: 50.3 ± 12.1 years) were included. FSTL1 levels were measured and the rs1259293 region of the FSTL1 gene was subjected to polymorphism analysis. 1.5 Tesla MRI was used to obtain cardiac images. RESULTS: There were 15 active (6 F-9M) and 31 (22 F-9M) controlled patients. Active patients had a higher left ventricular mass (LVM) and left ventricular mass index (LVMi). GH levels were positively correlated with left ventricular end-diastolic volume index (LVEDVi), stroke volume index (SVi), cardiac index (Ci), LVM and LVMi; r = 0.35, 0.38, 0.34, 0.39 and 0.39, respectively. IGF-1 index was positively correlated with LVEDVi, left ventricular end-systolic volume index (LVESVi), SVi, Ci, LVM and LVMi; r = 0.36, 0.34, 0.32, 0.31, 0.42 and 0.42, respectively. Twenty out of 46 patients with acromegaly (43.5%) had myocardial fibrosis. FSTL1 levels were neither correlated with disease activity nor with any functional and structural cardiac parameter. Multivariate linear regression analysis revealed no association between FSTL1 and any study parameters. The rs1259293 variant genotype CC was significantly associated with low left ventricular mass. CONCLUSIONS: Serum FSTL1 levels are not associated with functional and structural measures of myocardium in patients with acromegaly. However, the risk of left ventricular hypertrophy is reduced in CC genotyped individuals of FSTL1.

Long-term effect of conventional phosphate and calcitriol treatment on metabolic recovery and catch-up growth in children with PHEX mutation.

OBJECTIVES: Hereditary hypophosphatemic rickets (HR) is conventionally treated with phosphate and calcitriol. Exploring genotype and phenotypic spectrum of X-linked hypophosphatemic rickets (XLHR), focusing on short-term, long-term, and pubertal impact of conventional treatment was aimed. METHODS: Sixteen patients from 12 unrelated families with HR were analyzed for phosphate regulating endopeptidase homolog X-linked (PHEX) mutation. Initially Sanger sequencing analysis was performed. If PHEX mutation was not detected, multiplex ligation-dependent probe amplification (MLPA) was performed. If molecular defect was detected, first-degree relatives were analyzed. Thirteen patients (81%) and five first-degree relatives with XLHR were evaluated for genotype-phenotype or gender-phenotype correlation. Clinical characteristics and response to conventional treatment were determined retrospectively. RESULTS: Nine different PHEX mutations were identified; four splice-site, three point mutations, and two single exon deletions. Four were novel mutations. Despite conventional treatment, median adult height was lower than median height on admission (-3.8 and -2.3 SDS, respectively), metabolic and radiographic recovery were not achieved, adherence was low (30%). Although mean adult height was better in compliant patients than noncompliants (-2.6 vs. -3.7 SDS, respectively), they were still short. Correlation between phenotype and genotype or gender could not be shown. Median phosphate decreased significantly throughout puberty (p=0.014). Median pubertal height was lower than prepubertal height (-4.4 vs. -3.6 SDS; respectively), pubertal growth spurt was not observed. Among five patients with a follow-up longer than five years, three had nephrocalcinosis (60%), two had hyperparathyroidism (40%), 4/6 (33%) required correction osteotomy. CONCLUSIONS: Conventional treatment appears to have limited effect on metabolic, clinical and radiographic recovery in XLHR. Metabolic control and growth worsened during puberty. Although, long-term adverse effects are yet to be seen, introduction of burosumab as first-line treatment may be an alternative after infancy.

Further expanding the mutational spectrum of brain abnormalities, neurodegeneration, and dysosteosclerosis: A rare disorder with neurologic regression and skeletal features.

Colony stimulating factor 1 receptor (CSF1R, MIM# 164770) encodes a tyrosine-kinase receptor playing an important role in development of osteoclasts and microglia. Heterozygous CSF1R variants have been known to cause hereditary diffuse leukoencephalopathy with spheroids (HDLS, MIM# 221820), an adult-onset leukoencephalopathy characterized by loss of motor functions and cognitive decline. Recently, a new phenotype characterized by brain abnormalities, neurodegeneration, and dysosteosclerosis (BANDDOS) with biallelic CSF1R pathogenic variants in the etiology has been described. BANDDOS differs from HDLS by early-onset neurodegenerative changes with additional structural brain abnormalities and skeletal findings resembling dysosteosclerosis (DOS). Described skeletal findings of the disease are highly variable ranging from absence of a skeletal phenotype and milder Pyle disease-like to osteopetrosis and DOS. To date, only a few patients carrying biallelic CSF1R variants have been reported. In this clinical report, we describe three siblings with variable skeletal findings along with neurological symptoms ranging from mild to severe in whom exome sequencing revealed a novel homozygous splice site variant in canonical splice donor site of intron 21 adjacent to an exon, which encoding part of kinase domain of CSF1R along with a review of the literature.

Genetic disorders with symptoms mimicking rheumatologic diseases: A single-center retrospective study.

Musculoskeletal symptoms may be due to noninflammatory causes, including genetic disorders. We aimed to examine the final genetic diagnosis in patients who presented with musculoskeletal complaints to the rheumatology department. Patients who presented to the Department of Pediatric Rheumatology and were referred to the pediatric genetic department between January 2015 and May 2019 were evaluated retrospectively. A total of 60 patients, 19 boys (31.66%), with a mean age of 12.46 ± 1.41 years were included in the study. The total consanguinity rate was 25%. The most common (29.5%) cause of referral to the pediatric genetic department was the presence of skeletal anomalies (such as camptodactyly, clinodactyly, and short stature) with accompanying joint findings. Approximately one-third of the patients (n: 19) were diagnosed and followed up by the pediatric genetics department. The diagnoses of patients were as follows: camptodactyly, arthropathy, coxa vara, and pericarditis (CACP) syndrome (n: 3); trichorhinophalangeal syndrome (n: 1); progressive pseudorheumatoid dysplasia (n: 2); LIG4 syndrome (n: 1); H syndrome (n: 1); spondyloenchondrodysplasia (SPENCD) (n: 3); and nonspecific connective tissue disorders (n: 8). In the differential diagnosis of patients who are referred to the Department of Pediatric Rheumatology with complaints of the musculoskeletal system, genetic disorders should also be considered.

Whole exome sequencing in unclassified autoinflammatory diseases: more monogenic diseases in the pipeline?

OBJECTIVE: Autoinflammatory diseases (AIDs) are characterized by recurrent sterile systemic inflammation attacks. More than half of the patients remain genetically undiagnosed with next-generation sequencing panels for common AIDs. In this study, we aimed to define phenotype-genotype correlations in a cohort of unclassified AID patients via whole exome sequencing (WES). METHODS: Patients with features of AIDs were included in this study followed in the Department of Pediatric Rheumatology at Hacettepe University. They were first screened for MEFV with Sanger sequencing and then WES performed for the patients with clinically insignificant results. Pre-analysis of WES data was done by considering the 13 most common AID-related genes. Further bioinformatic analysis was performed if the patient remained genetically undiagnosed. RESULTS: The median age at disease onset was 1.2 years (range 0.2-16) and at the time of study recruitment was 14 years (range 3.5-17). In our cohort, WES provided a definite or probable disease-causing variant in 4 of 11 patients (36%). Heterozygous mutations for two of these genes were previously associated with neurological defects (ADAM17, TBK1), also homozygous ADAM17 mutations were observed in one family with neonatal inflammatory skin and bowel disease. Besides, two genes (LIG4, RAG1) were associated with immunodeficiency although the patients had presented with inflammatory features. Finally, for one patient, we associated a strong candidate gene (NLRC3) with autoinflammatory features. CONCLUSION: WES strategy is cost-effective and provides substantial results for a selected group of undefined AID patients. Our results will contribute to the spectrum of unclassified AIDs.

Klotho gene G395A and C1818T polymorphisms in acromegaly: Association with clinical presentation and comorbidities.

BACKGROUND: Klotho is a new identified anti-ageing gene with tumour suppressor activities. Current data suggest that there is a tight relationship between Klotho protein and growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis. PURPOSE: This study aimed to investigate the possible association of Klotho gene polymorphisms with acromegaly and to assess whether these polymorphisms contribute to clinical characteristics, comorbidities and biochemical variables in these patients. METHODS: The study included 52 patients with acromegaly and 52 unrelated healthy subjects. The Klotho G395A and C1818T polymorphisms were assessed by Sanger sequencing. Serum levels of sKlotho were determined by ELISA method. RESULTS: Subjects carrying GA genotype of Klotho G395A polymorphism had 3.27 times higher risk of developing acromegaly [odds ratio (OR), 3.27; 95% confidence interval (CI): 1.37-7.81; p = .023]. The A allele of G395A was significantly associated with acromegaly risk (OR, 2.27; 95% CI: 1.1-4.72; p = .022). No association was observed between the studied polymorphisms and disease characteristics including age at acromegaly diagnosis, size of adenoma, baseline GH and IGF-1 concentrations, and final outcome. G395A polymorphism was associated with the presence of malignancy (OR, 2.24, 95% CI: 1.63-3.08; p = .019) and colorectal polyps (OR, 1.99; 95% CI: 1.02-3.88; p = .047) in patients with acromegaly. Serum sKlotho levels were significantly higher and correlated with GH and IGF-1 levels among acromegaly patients. There was no association between the studied polymorphisms and sKlotho levels. CONCLUSIONS: Klotho G395A polymorphism is associated with acromegaly susceptibility and increased risk of malignancy and colorectal polyps in these patients.

FTO gene-lifestyle interactions on serum adiponectin concentrations and central obesity in a Turkish population.

The aim of the study was to investigate whether lifestyle factors modify the association between fat mass and obesity-associated (FTO) gene single nucleotide polymorphisms (SNPs) and obesity in a Turkish population. The study included 400 unrelated individuals, aged 24-50 years recruited in a hospital setting. Dietary intake and physical activity were assessed using 24-hour dietary recall and self-report questionnaire, respectively. A genetic risk score (GRS) was developed using FTO SNPs, rs9939609 and rs10163409. Body mass index and fat mass index were significantly associated with FTO SNP rs9939609 (p = 0.001 and p = 0.002, respectively) and GRS (p = 0.002 and p = 0.003, respectively). The interactions between SNP rs9939609 and physical activity on adiponectin concentrations, and SNP rs10163409 and dietary protein intake on increased waist circumference were statistically significant (Pinteraction = 0.027 and Pinteraction = 0.044, respectively). Our study has demonstrated that the association between FTO SNPs and central obesity might be modified by lifestyle factors in this Turkish population.

Hyperinsulinemic Hypoglycemia in a Patient with Costello Syndrome: An Etiology to Consider in Hypoglycemia.

Several endocrine disorders have been defined in patients with Costello syndrome (CS). In this report, we describe a patient with CS accompanied by a clinical picture of hyperinsulinemic hypoglycemia responsive to diazoxide treatment. A 41-day-old female patient with a birth weight of 3,600 g was referred for atypical facial features and swallowing dysfunction. She had a weight of 4,000 g (-0.8 SDS), a length of 50 cm (-2.4 SDS), and a head circumference of 38 cm (0.2 SDS). The clinical findings were suggestive of a genetic syndrome, mainly a RASopathy or Beckwith-Wiedemann syndrome. Whole exome sequencing revealed a de novo heterozygous missense variant in the HRAS (NM_001130442) gene in exon 2: c.35G>C; p.(Gly12Ala), establishing the molecular diagnosis of CS. The patient developed symptomatic hypoglycemia (jitteriness and sweating) at the age of 13 months. The patient's serum glucose was 38 mg/dL with simultaneous serum insulin and C-peptide levels, 2.8 µIU/mL and 1.8 ng/mL, respectively. Hyperinsulinism was suspected, and an exaggerated glucose response was detected in a glucagon test. Blood glucose monitoring indicated episodes of fasting hypoglycemia and postprandial hyperglycemia. Diazoxide of 10 mg/kg/day was initiated in 3 doses for hyperinsulinemic hypoglycemia, which resolved without new episodes of postprandial hyperglycemia. The patient deceased at the age of 17 months due to cardiorespiratory failure in the course of severe pneumonia complicated with pulmonary hypertension and hypertrophic cardiomyopathy. Several genetic syndromes including CS are associated with endocrinologic manifestations including abnormal glucose homeostasis. Although the frequency and underlying mechanisms leading to hyperinsulinemic hypoglycemia are yet unknown, hypoglycemia in CS responds well to diazoxide.

Novel insights into diabetes mellitus due to DNAJC3-defect: Evolution of neurological and endocrine phenotype in the pediatric age group.

BACKGROUND: A number of inborn errors of metabolism caused by abnormal protein trafficking that lead to endoplasmic reticulum storage diseases (ERSD) have been defined in the last two decades. One such disorder involves biallelic mutations in the gene encoding endoplasmic reticulum resident co-chaperone DNAJC3 (P58IPK ) that leads to diabetes in the second decade of life, in addition to multiple endocrine dysfunction and nervous system involvement. OBJECTIVE: The aim of this study was to define the natural history of this new form of diabetes, especially the course of abnormalities related to glucose metabolism. METHODS: Whole-exome and Sanger sequencing was used to detect DNAJC3 defect in two patients. Detailed analysis of their clinical history as well as biochemical, neurological and radiological studies were carried out to deduce natural history of neurological and endocrine phenotype. RESULTS: DNAJC3 defect led to beta-cell dysfunction causing hyperinsulinemichypoglycemia around 2 years of age in both patients, which evolved into diabetes with insulin deficiency in the second decade of life, probably due to beta cell loss. Endocrine phenotype involved severe early-onset growth failure due to growth hormone deficiency, and hypothyroidism of central origin. Neurological phenotype involved early onset sensorineural deafness discovered around 5 to 6 years, and neurodegeneration of central and peripheral nervous system in the first two decades of life. CONCLUSION: Biallelic loss-of-function in the ER co-chaperone DNAJC3 leads to a new form of diabetes with early onset hyperinsulinemic hypoglycemia evolving into insulin deficiency as well as severe growth failure, hypothyroidism and diffuse neurodegeneration.

Poikiloderma with Neutropenia, Clericuzio-Type Accompanied by Loss of Digits Due to Severe Osteomyelitis.

Poikiloderma with neutropenia (PN), Clericuzio-type is a rare autosomal recessively transmitted genodermatosis caused by biallelic mutations in the USB1 gene and is characterized by early-onset poikiloderma and chronic neutropenia. Nail dystrophy, palmoplantar hyperkeratosis, hypogonadotropic hypogonadism, and recurrent infections can be associated with the disease. Herein, we present a 27-year-old Turkish male patient newly diagnosed as PN, Clericuzio-type after confirmation of a c.531delA (p.His179MetfsX86) homozygous deleterious mutation in exon 5 of the USB1 gene. The presented case highlights the importance of genetic testing for avoiding misdiagnosis based solely on clinical findings, as well as the benefit of a multi-disciplinary diagnostic approach, as he was initially misdiagnosed as Rothmund-Thompson syndrome and subsequently diagnosed as PN, Clericuzio-type at age 27 years.

A Revisited Diagnosis of Collagen VI Related Muscular Dystrophy in a Patient with a Novel COL6A2 Variant and 21q22.3 Deletion.

The genetic etiology of collagen VI related muscular dystrophies is heterogenous. Genomic deletions in one allele involving COL6A2 or both COL6A1 and COL6A2 unmasking a pathogenic variant in the second nondeleted allele have been described in the etiology. We aimed to report the clinical and molecular findings of a 13-year-old boy with ring chromosome 21 who presented to our clinic with easy fatigability, muscle weakness, and waddling gait. Phenotypic delineation along with chromosomal microarray analysis and DNA sequencing were performed. Affymetrix CytoScan Optima array platform and DNA sequencing revealed a 2,202 kb de novo deletion at 21q22.3, including COL6A1 and COL6A2, and a novel heterozygous variant at position c.2875G > A;p.(Glu959Lys) in COL6A2, respectively. Before his admission to our center, the patient was evaluated for hypotonia elsewhere when he was 15 months old. He was diagnosed with ring chromosome 21 on peripheral blood karyotype analysis; however, no further assessment was performed at that time. He had normal growth with mild dysmorphic facial features, distal laxity, gastrocnemius hypertrophy, proximal muscle weakness, increased lordotic posture with mild flexion contractures at the knees, and gait disturbance. Although the phenotype does not fit into classical Ullrich congenital muscular dystrophies, muscle magnetic resonance imaging (MRI) revealed a complementary pattern consistent with collagen VI related myopathies. Genetic testing confirmed the clinical diagnosis as well. This patient yet represents another example of the effect of large genomic deletions leading to recessive disorders through unmasking a pathogenic variant in the second nondeleted allele.

Further Phenotypic Delineation of Partial Trisomy 17q and Partial Monosomy 20q due to Rare t(17;20).

Copy number variations in subtelomeric regions of chromosomes 17 and 20 are associated with intellectual disability and various systemic manifestations. Microarray analysis allows identification of submicroscopic chromosomal abnormalities and is applicable to elucidate the etiology of cognitive impairment in approximately one-fifth of the cases. In the present study, we report on 3 male children from 2 sisters, who suffered from intellectual disability, facial dysmorphism, and epilepsy. Despite the initial suggestion of an X-linked inheritance, the condition was associated with 17q25.3 duplication and concomitant 20q13.33 deletion, as detected by microarray analysis. Coexistence of a deletion and a duplication suggests unbalanced segregation of a parental balanced translocation. Further investigations revealed maternal balanced translocations, which resulted in copy number aberrations in the children following unbalanced segregations. The work-up underlined the importance of genomic screening using microarrays as the first-tier diagnostic tool in intellectual disability, despite an apparent X-linked segregation in the pedigree.

Atypical Presentation of Sengers Syndrome: A Novel Mutation Revealed with Postmortem Genetic Testing.

INTRODUCTION: Sengers syndrome is an autosomal recessive disorder characterized by congenital cataracts, hypertrophic cardiomyopathy, skeletal myopathy and lactic acidosis. The causative AGK mutations have been identified with whole exome sequencing. CLINICAL REPORT: We report on a 9-month-old infant with episodic lactic acidosis who died before a definitive diagnosis could be established. Postmortem genomic autopsy revealed a novel homozygous NM_018238: c.1215dupG; p.Phe406Valfs*4 mutation in AGK (OMIM 610345) confirming the diagnosis of Sengers syndrome. CONCLUSION: This report provides further evidence that reverse genetics is a useful approach in patients who do not manifest the hallmark features of known and recognizable syndromes.

Molecular Etiology of Isolated Congenital Cataract Using Next-Generation Sequencing: Single Center Exome Sequencing Data from Turkey.

Congenital cataract, which refers to lenticular opacity diagnosed at birth or more commonly during the first year of life, is one of the leading causes of childhood blindness. Molecular understanding of the disease pathogenesis has evolved thanks to many studies based on modern technologies. In this study, we aimed to identify and discuss the molecular etiology of nonsyndromic or nonmetabolic bilateral congenital cataract by whole-exome sequencing (WES). Patients with bilateral congenital cataract presumed to be isolated after metabolic and genetic evaluation were enrolled in the study. All patients underwent detailed ophthalmological examination and bilateral cataract surgery. DNA samples of the probands, parents, and available affected family members were analyzed by WES. Variants were validated and confirmed by Sanger sequencing in all probands and in available affected family members. A total of 4 patients (3 girls and 1 boy) were recruited. Two patients had nuclear, 1 patient had total, and 1 patient had combined lamellar and sutural cataract. One family had consanguinity. A heterozygous c.215+1G>A mutation in CRYBA1, heterozygous c.432C>G (p.Tyr144Ter) mutation in CRYGC, heterozygous c.70A>C (p.Pro24Thr) mutation in CRYGD, and a heterozygous c.466G>A (p.Gly156Arg) mutation in CRYBB3 were detected. All these mutations were confirmed by Sanger sequencing in selected affected individuals. The current study identified all causative mutations of congenital cataract in the crystalline genes. The results confirmed that WES is a very useful tool in the investigation of the diseases with heterogeneous genetic background.

Genotype and phenotype evaluation of patients with primary ciliary dyskinesia: First results from Turkey.

BACKGROUND AND OBJECTIVE: Primary ciliary dyskinesia (PCD) is a rare and genetically heterogeneous disease and the severity of the disease related with genetic analysis has been described in some previous studies. The main aim of our study was to describe the clinical characteristics and laboratory findings of patients with genetically diagnosed PCD and to investigate the correlation between clinical, radiologic, and laboratory findings and genetic analyses of these patients. METHOD: This is a cohort study in which we analyzed the clinical characteristics, laboratory findings, and genetic results of 46 patients with genetically diagnosed PCD through whole-exome sequencing at our single center from a total of 265 patients with PCD within a 5-year period. RESULTS: Genetic analysis revealed pathogenic variants in DNAH5 (n = 12 individuals, 12 families), CCDC40 (n = 9 individuals, six families), RSPH4A (n = 5 individuals, three families), DNAH11 (n = 4 individuals, four families), HYDIN (n = 5 individuals, five families), CCNO (n = 4 individuals, four families), DNAI1 (n = 2 individuals, one family), ARMC4 (n = 2 individuals, two families), TTC25 (n = 1), DNAH1 (n = 1), and CCDC39 (n = 1) genes. Although not statistically significant, the age at diagnosis was lower (median: 3 years; range, 6 months-4 years) in patients with CCNO pathogenic variants due to the early reporting of symptoms, and the median body mass index (BMI) and BMI z scores were lower in patients at 18.7 and 16 kg/m2 , and -0.78 and -1.2 with CCDC40 and CCNO pathogenic variants, respectively. The median forced expiratory flow in 1 second (FEV1%), forced vital capacity (FVC%), and forced expiratory flow (FEF)25-75% were 53%, 64%, and 28%, respectively; these parameters were also lower in the CCDC40 group than in the other groups. There was no significant correlation between the genetic results and symptoms, radiologic findings, and microbiologic data of patients with PCD. CONCLUSION: In PCD, there was significant heterogeneity of lung disease, patients who had pathogenic variants in CCNO presented earlier, and those with CCDC40 and CCNO had worse lung disease, and poorer nutritional status compared with the other subgroups. We hope that whole genotype-phenotype and clinical relationships will be identified in PCD.

ADA2 deficiency in a patient with Noonan syndrome-like disorder with loose anagen hair: The co-occurrence of two rare syndromes.

Noonan syndrome-like disorder with loose anagen hair (NS/LAH) is one of the RASopathies, a group of clinically related developmental disorders caused by germline mutations in genes that encode components acting in the RAS/MAPK pathway. Among RASopathies, NS/LAH (OMIM 607721) is an extremely rare, multiple anomaly syndrome characterized by dysmorphic facial features similar to those observed in Noonan syndrome along with some distinctive ectodermal findings including easily pluckable, sparse, thin, and slow-growing hair. ADA2 deficiency (DADA2, OMIM 615688) is a monogenic autoinflammatory disorder caused by homozygous or compound heterozygous mutations in ADA2, with clinical features including recurrent fever, livedo racemosa, hepatosplenomegaly, and strokes as well as immune dysregulation. This is the first report of NS/LAH and ADA2 deficiency in the same individual. We report on a patient presenting with facial features, recurrent infections and ectodermal findings in whom both the clinical and molecular diagnoses of NS/LAH and ADA2 deficiency were established, respectively.