The clinical phenotype of Koolen-de Vries syndrome in Turkish patients and literature review.

Koolen-de Vries syndrome (KdVS) is a rare multisystemic disorder caused by a microdeletion on chromosome 17q21.31 including KANSL1 gene or intragenic pathogenic variants in KANSL1 gene. Here, we describe the clinical and genetic spectrum of eight Turkish children with KdVS due to a de novo 17q21.31 deletion, and report on several rare/new conditions. Eight patients from unrelated families aged between 17 months and 19 years enrolled in this study. All patients evaluated by a clinical geneticist, and the clinical diagnosis were confirmed by molecular karyotyping. KdVS patients had some common distinctive facial features. All patients had neuromotor retardation, and speech and language delay. Epilepsy, structural brain anomalies, ocular, ectodermal, and musculoskeletal findings, and friendly personality were remarkable in more than half of the patients. Hypertension, hypothyroidism, celiac disease, and postaxial polydactyly were among the rare/new conditions. Our study contributes to the clinical spectrum of patients with KdVS, while also provide a review by comparing them with previous cohort studies.

Clinical and molecular evaluation of MEFV gene variants in the Turkish population: a study by the National Genetics Consortium.

Familial Mediterranean fever (FMF) is a monogenic autoinflammatory disorder with recurrent fever, abdominal pain, serositis, articular manifestations, erysipelas-like erythema, and renal complications as its main features. Caused by the mutations in the MEditerranean FeVer (MEFV) gene, it mainly affects people of Mediterranean descent with a higher incidence in the Turkish, Jewish, Arabic, and Armenian populations. As our understanding of FMF improves, it becomes clearer that we are facing with a more complex picture of FMF with respect to its pathogenesis, penetrance, variant type (gain-of-function vs. loss-of-function), and inheritance. In this study, MEFV gene analysis results and clinical findings of 27,504 patients from 35 universities and institutions in Turkey and Northern Cyprus are combined in an effort to provide a better insight into the genotype-phenotype correlation and how a specific variant contributes to certain clinical findings in FMF patients. Our results may help better understand this complex disease and how the genotype may sometimes contribute to phenotype. Unlike many studies in the literature, our study investigated a broader symptomatic spectrum and the relationship between the genotype and phenotype data. In this sense, we aimed to guide all clinicians and academicians who work in this field to better establish a comprehensive data set for the patients. One of the biggest messages of our study is that lack of uniformity in some clinical and demographic data of participants may become an obstacle in approaching FMF patients and understanding this complex disease.

Coexistence of a Homozygous Chromosome 4q35.2 Deletion and Hidden IQSEC2 Pathogenic Variant in a Child with Intellectual Disability.

Terminal deletions in the long arm of chromosome 4 are an uncommon event, with a worldwide incidence of approximately 0.001%. The majority of these deletions occur de novo. Terminal deletion cases are usually accompanied by clinical findings that include facial and cardiac anomalies, as well as intellectual disability. In this study, we describe the case of a 2-year-old girl, the fourth child born to consanguineous parents. While her karyotype was normal, a homozygous deletion was identified in the chromosome 4q35.2 region by subtelomeric FISH. A heterozygous deletion of the chromosome 4q35.2 region was observed in both parents. According to the literature, this is the first report of a case that has inherited a homozygous deletion of chromosome 4qter from carrier parents. Subsequent array-CGH analyses were performed on both the case and her parents. Whole-exome sequencing was also carried out to determine potential variants. We detected a NM_001111125.3:c.2329G>T (p.Glu777Ter) nonsense variant of the IQSEC2 gene in the girl, a variant that is related to X-linked intellectual disability.

Further defining the clinical and molecular spectrum of acromesomelic dysplasia type maroteaux: a Turkish tertiary center experience.

Acromesomelic dysplasia type Maroteaux (AMDM, OMIM #602875) is an autosomal recessive disorder characterized by severe short stature, shortened middle and distal segments of the limbs, redundant skin of fingers, radial head subluxation or dislocation, large great toes and cranium, and normal intelligence. Only the skeletal system appears to be consistently affected. AMDM is caused by biallelic loss-of-function variants in the natriuretic peptide receptor B (NPRB or NPR2, OMIM #108961) which is involved in endochondral ossification and longitudinal growth of limbs and vertebrae. In this study, we investigated 26 AMDM patients from 22 unrelated families and revealed their genetic etiology in 20 families, via Sanger sequencing or exome sequencing. A total of 22 distinct variants in NPR2 (14 missense, 5 nonsense, 2 intronic, and 1 one-amino acid deletion) were detected, among which 15 were novel. They were in homozygous states in 19 patients and in compound heterozygous states in four patients. Parents with heterozygous NPR2 variants were significantly shorter than the control. Extra-skeletal abnormalities, including global developmental delay/intellectual disability, nephrolithiasis, renal cyst, and oligodontia were noted in the patient cohort. The high parental consanguinity rate might have contributed to these findings, probably associated with other gene variants. This study represents the largest cohort of AMDM from Turkey and regional countries and further expands the molecular and clinical spectrum of AMDM.

Skeletal and molecular findings in 51 Cleidocranial dysplasia patients from Turkey.

Loss or decrease of function in runt-related transcription factor 2 encoded by RUNX2 is known to cause a rare autosomal-dominant skeletal disorder, cleidocranial dysplasia (CCD). Clinical spectrum and genetic findings in 51 CCD patients from 30 unrelated families are herein presented. In a majority of the patients, facial abnormalities, such as delayed fontanel closure (89%), parietal and frontal bossing (80%), metopic groove (77%), midface hypoplasia (94%), and abnormal mobility of shoulders (90%), were recorded following clinical examination. In approximately one-half of the subjects, wormian bone (51%), short stature (43%), bell-shaped thorax (42%), wide pubic symphysis (50%), hypoplastic iliac wing (59%), and chef's hat sign (44%) presented in available radiological examinations. Scoliosis was identified in 28% of the patients. Investigation of RUNX2 revealed small sequence alterations in 90% and gross deletions in 10% of the patients; collectively, 23 variants including 11 novel changes (c.29_30insT, c.203delAinsCG, c.423 + 2delT, c.443_454delTACCAGATGGGAinsG, c.505C > T, c.594_595delCTinsG, c.636_637insC, c.685 + 5G > A, c.1088G > T, c.1281delC, Exon 6-9 deletion) presented high allelic heterogeneity. Novel c.29_30insT is unique in affecting the P1-driven long isoform of RUNX2, which is expected to disrupt the N-terminal region of RUNX2; this was shown in two unrelated phenotypically discordant patients. The clinical findings highlighted mild intra-familial genotype-phenotype correlation in our CCD cohort.

A clinical scoring system for congenital contractural arachnodactyly.

PURPOSE: Congenital contractural arachnodactyly (CCA) is an autosomal dominant connective tissue disorder manifesting joint contractures, arachnodactyly, crumpled ears, and kyphoscoliosis as main features. Due to its rarity, rather aspecific clinical presentation, and overlap with other conditions including Marfan syndrome, the diagnosis is challenging, but important for prognosis and clinical management. CCA is caused by pathogenic variants in FBN2, encoding fibrillin-2, but locus heterogeneity has been suggested. We designed a clinical scoring system and diagnostic criteria to support the diagnostic process and guide molecular genetic testing. METHODS: In this retrospective study, we assessed 167 probands referred for FBN2 analysis and classified them into a FBN2-positive (n = 44) and FBN2-negative group (n = 123) following molecular analysis. We developed a 20-point weighted clinical scoring system based on the prevalence of ten main clinical characteristics of CCA in both groups. RESULTS: The total score was significantly different between the groups (P < 0.001) and was indicative for classifying patients into unlikely CCA (total score <7) and likely CCA (total score ≥7) groups. CONCLUSIONS: Our clinical score is helpful for clinical guidance for patients suspected to have CCA, and provides a quantitative tool for phenotyping in research settings.

Overlapping SETBP1 gain-of-function mutations in Schinzel-Giedion syndrome and hematologic malignancies.

Schinzel-Giedion syndrome (SGS) is a rare developmental disorder characterized by multiple malformations, severe neurological alterations and increased risk of malignancy. SGS is caused by de novo germline mutations clustering to a 12bp hotspot in exon 4 of SETBP1. Mutations in this hotspot disrupt a degron, a signal for the regulation of protein degradation, and lead to the accumulation of SETBP1 protein. Overlapping SETBP1 hotspot mutations have been observed recurrently as somatic events in leukemia. We collected clinical information of 47 SGS patients (including 26 novel cases) with germline SETBP1 mutations and of four individuals with a milder phenotype caused by de novo germline mutations adjacent to the SETBP1 hotspot. Different mutations within and around the SETBP1 hotspot have varying effects on SETBP1 stability and protein levels in vitro and in in silico modeling. Substitutions in SETBP1 residue I871 result in a weak increase in protein levels and mutations affecting this residue are significantly more frequent in SGS than in leukemia. On the other hand, substitutions in residue D868 lead to the largest increase in protein levels. Individuals with germline mutations affecting D868 have enhanced cell proliferation in vitro and higher incidence of cancer compared to patients with other germline SETBP1 mutations. Our findings substantiate that, despite their overlap, somatic SETBP1 mutations driving malignancy are more disruptive to the degron than germline SETBP1 mutations causing SGS. Additionally, this suggests that the functional threshold for the development of cancer driven by the disruption of the SETBP1 degron is higher than for the alteration in prenatal development in SGS. Drawing on previous studies of somatic SETBP1 mutations in leukemia, our results reveal a genotype-phenotype correlation in germline SETBP1 mutations spanning a molecular, cellular and clinical phenotype.

Coronal craniosynostosis due to TCF12 mutations in patients from Turkey.

Craniosynostosis consists of premature fusion of one or more cranial sutures and can be seen as part of a syndrome or diagnosed as nonsyndromic (isolated). Although more than 180 craniosynostosis syndromes have been identified, 70% of the cases are diagnosed as nonsyndromic. On the other hand, genetic causes of the cases are mostly unknown and the overall frequency of the genetic diagnosis is around 25%. In this study, we used targeted Next Generation Sequencing (NGS) analysis to identify the genetic variations of two craniosynostosis cases. We have identified two different truncating mutations, a known NM_207036.1:c.778_779delAT;p.(Met260Valfs*5) and a novel NM_207036.1:c.1102_1108delTCACCTC;p.(Pro369Glnfs*26) TCF12 variants. Additionally, upon physical examination of these two cases, we have observed some shared clinical similarities as well as differences such as bilateral simian crease and hidden cleft palate. This is the first study that reports the TCF12 mutations in Turkish patients with coronal suture synostosis.

A subset of patients with acquired partial lipodystrophy developing severe metabolic abnormalities.

Purpose/Aim of the study: Acquired partial lipodystrophy (APL) is a rare disease characterized by selective loss of adipose tissue. In this study, we aimed to present a subset of patients with APL, who developed severe metabolic abnormalities, from our national lipodystrophy registry. MATERIALS AND METHODS: Severe metabolic abnormalities were defined as: poorly controlled diabetes (HbA1c above 7% despite treatment with insulin more than 1 unit/kg/day combined with oral antidiabetics), severe hypertriglyceridemia (triglycerides above 500 mg/dL despite treatment with lipid-lowering drugs), episodes of acute pancreatitis, or severe hepatic involvement (biopsy-proven non-alcoholic steatohepatitis (NASH)). RESULTS: Among 140 patients with all forms of lipodystrophy (28 with APL), we identified 6 APL patients with severe metabolic abnormalities. The geometric mean for age was 37 years (range: 27-50 years; 4 females and 2 males). Five patients had poorly controlled diabetes despite treatment with high-dose insulin combined with oral antidiabetics. Severe hypertriglyceridemia developed in five patients, of those three experienced episodes of acute pancreatitis. Although all six patients had hepatic steatosis at various levels on imaging studies, NASH was proven in two patients on liver biopsy. Our data suggested that APL patients with severe metabolic abnormalities had a more advanced fat loss and longer disease duration. CONCLUSIONS: We suggest that these patients represent a potential subgroup of APL who may benefit from metreleptin or investigational therapies as standard treatment strategies fail to achieve a good metabolic control.

MPZL2 is a novel gene associated with autosomal recessive nonsyndromic moderate hearing loss.

While recent studies have revealed a substantial portion of the genes underlying human hearing loss, the extensive genetic landscape has not been completely explored. Here, we report a loss-of-function variant (c.72delA) in MPZL2 in three unrelated multiplex families from Turkey and Iran with autosomal recessive nonsyndromic hearing loss. The variant co-segregates with moderate sensorineural hearing loss in all three families. We show a shared haplotype flanking the variant in our families implicating a single founder. While rare in other populations, the allele frequency of the variant is ~ 0.004 in Ashkenazi Jews, suggesting that it may be an important cause of moderate hearing loss in that population. We show that Mpzl2 is expressed in mouse inner ear, and the protein localizes in the auditory inner and outer hair cells, with an asymmetric subcellular localization. We thus present MPZL2 as a novel gene associated with sensorineural hearing loss.

A novel AXIN2 gene mutation in sagittal synostosis.

The bones of the skull are held together by fibrous joints called sutures. Premature fusion of these sutures leads to a pathologic condition called as craniosynostosis. Although at least 50 nuclear genes including FGFR2, TWIST1, TCF12, and SMAD6 were identified as causative of craniosynostosis; only 25% of the patients can be genetically diagnosed. Here, we report a 3-year-old Turkish Caucasian boy with sagittal craniosynostosis with a de novo loss-of-function mutation in exon 4 of the AXIN2 gene for the first time. The patient has frontal bossing, high anterior hair line, depressed nasal bridge, bilateral epicanthus and low set ears which are correlated with his scaphocephaly. As a negative regulator of the Wnt signaling pathway which is one of the key modulators of craniosynostosis syndrome, it has been shown in model organisms that Axin2 orchestrates the regulation of beta-catenin especially in the intramembranous ossification process. This clinical report adds value to the literature that AXIN2 gene mutations could be a potential cause in human calvarial malformations, especially for the sagittal synostosis.

Bone mineral density in patients with mucopolysaccharidosis type III.

Mucopolysaccharidosis type III (MPS III) is a neurodegenerative disorder. In MPS III patients, heparan sulfate accumulates in many tissues especially the central nervous system. There are limited data regarding bone involvement in MPS III compared to other MPS types. The aim of this study was to evaluate bone mineral density (BMD) and the prevalence of low bone mass, and to explore the association between BMD, vitamin D levels, bone fracture, and patient characteristics in MPS III. A clinical assessment and interview was held to obtain data about family history, height, weight, body mass index (BMI), nutrition, walking capacity, bone fracture, epilepsy, and medical therapy of 15 patients with MPS III. Height, weight, and BMI z scores were calculated. Laboratory tests including 25-hydroxyvitamin D (25-OH-D) were measured. BMD measurements for the lumbar spine were obtained using dual-energy X-ray absorptiometry (DXA). BMD z scores were adjusted for height-for-age z score (HAZ) to provide correction for height deficits. Lumbar spine BMD z score was low (<-1) in five patients for chronological age and normalized in two of five patients after adjustment for HAZ. Three patients continued to have low BMD; these were older than the other patients and one had a history of long bone fracture. Two of these patients were observed to have lost walking capacity at 10 and 14 years, and the other was walking with support. Six patients had deficient, and three patients had insufficient levels of 25-OH-D. Two osteoporotic patients had significantly lower levels of 25-OH-D. We found that older patients with immobility are at high risk of osteoporosis and bone fracture, and vitamin D deficiencies/insufficiencies are widely seen. We recommend monitoring BMD by DXA and checking vitamin D metabolism to assess low bone mass and fracture risk in older MPS III patients with immobility.

Perinatal Diagnostic Approach to Fetal Skeletal Dysplasias: Six Years Experience of a Tertiary Center.

Skeletal dysplasias (SDs) constitute a group of heterogeneous disorders affecting growth morphology of the chondro-osseous tissues. Prenatal diagnosis of SD is a considerable clinical challenge due to phenotypic variability. We performed a retrospective analysis of the fetal autopsies series conducted between January 2006 and December 2012 at our center. SD was detected in 54 (10%) out of 542 fetal autopsy cases which included; 11.1% thanatophoric dysplasia (n = 6), 7.4% achondroplasia (n = 4), 3.7% osteogenesis imperfect (n = 2), 1.9% Jarcho-Levin Syndrome (n = 1), 1.9% arthrogryposis (n = 1), 1.9% Dyggve-Melchior-Clausen syndrome (n = 1), 72.1% of dysostosis cases (n = 39). All SD cases were diagnosed by ultrasonography. In 20 of the cases, amniocentesis was performed, 4 cases underwent molecular genetic analyses. Antenatal identification of dysplasia is important in the management of pregnancy and in genetic counseling. Our data analysis showed that SD is usually detected clinically after the 20th gestational week. Genetic analyses for SD may provide early diagnosis and management.

Possible autosomal recessive inheritance in an infant with acrofacial dysostosis similar to Nager syndrome.

The acrofacial dysostosis syndromes, which are characterized by malformations of the craniofacial region and limbs, are a clinically heterogeneous group of disorders. Based primarily on the of the pattern of limb defects two major groups have emerged: Nager syndrome with predominantly preaxial malformations plus mandibulofacial dysostosis (severe micrognathia and malar hypoplasia) and Miller syndrome with postaxial malformations plus mandibulofacial dysostosis. Among these syndromes, Nager syndrome is a rare condition but the most common form of acrofacial dysostosis. Most cases are sporadic, while autosomal dominant and autosomal recessive inheritance patterns have been reported. Recently, heterozygous mutations in the SF3B4 gene on chromosome 1q12-q21 were found to be responsible for a subset of sporadic and autosomal dominant cases. We present a female infant born to consanguineous parents with craniofacial features resembling Nager syndrome and a unilateral preaxial limb malformation. Mutation analysis of coding exons of SF3B4 did not identify any mutations. This couple also had a deceased child who had similar clinical features. We conclude that, the presence of consanguinity and absence of mutation in SF3B4, provides evidence in support of a recessive form of Nager syndrome.

Expanding the clinical and molecular features of trichorhino- phalangeal syndrome with a novel variant.

BACKGROUND: Tricho-rhino-phalangeal syndrome (TRPS) is a rare, autosomal dominant disorder characterized by typical craniofacial features, ectodermal and skeletal findings. TRPS type 1 (TRPS1) is caused by pathogenic variations in the TRPS1 gene, which relates to the vast majority of cases. TRPS type 2 (TRPS2) is a contiguous gene deletion syndrome involving loss of functional copies of the TRPS1, RAD21, and EXT1. Herein, we reported the clinical and genetic spectrum of seven TRPS patients with a novel variant. We also reviewed the musculoskeletal and radiological findings in the literature. METHODS: Seven Turkish patients (three female, four male) from five unrelated families aged between 7 to 48 years were evaluated. The clinical diagnosis was confirmed by either molecular karyotyping or TRPS1 sequencing analysis via next-generation sequencing. RESULTS: Both TRPS1 and TRPS2 patients had some common distinctive facial features and skeletal findings. All patients had a bulbous nose with hypoplastic alae nasi, brachydactyly, short metacarpals and phalanges in variable stages. Low bone mineral density (BMD) was identified in two TRPS2 family members presenting with bone fracture, and growth hormone deficiency was detected in two patients. Skeletal X-ray imaging revealed cone-shaped epiphysis of the phalanges in all, and multiple exostoses were present in three patients. Cerebral hamartoma, menometrorrhagia and long bone cysts were among the new/rare conditions. Three pathogenic variants in TRPS1 were identified in four patients from three families, including a frameshift (c.2445dup, p.Ser816GlufsTer28), one missense (c.2762G > A), and a novel splice site variant (c.2700+3A > G). We also reported a familial inheritance in TRPS2 which is known to be very rare. CONCLUSIONS: Our study contributes to the clinical and genetic spectrum of patients with TRPS while also providing a review by comparing with previous cohort studies.

Phenotypic and Molecular Spectrum of a Turkish Cohort with Hereditary Multiple Osteochondromas.

OBJECTIVE: Hereditary multiple osteochondromas is an autosomal dominant disorder caused by heterozygous pathogenic variants in EXT1 or EXT2. We aimed to evaluate the clinical and molecular findings of a Turkish cohort with hereditary multiple osteochondroma. MATERIALS AND METHODS: Thirty-two patients aged 1.3-49.6 years from 22 families were enrolled. Genetic analyses were made by EXT1 and/or EXT2 sequencing and chromosomal microarray analyses. RESULTS: We found 17 intragenic pathogenic variants in EXT1 (13/17) and EXT2 (4/17), 12 of which are novel. Four probands had EXT1 deletions, including 2 patients with partial EXT1 microdeletions involving exons 2-11 and 5-11, and 2 patients with whole-gene deletions. In 21 variants, the frequency of truncating and missense variants was 76.1% and 23.8%, respectively. Two families had no detectable variants in EXT1 and EXT2. All patients had multiple osteochondromas at the long bones, mainly at the tibia, forearm, femur, and humerus. Bowing deformity of the forearms (9/32) and the lower extremities (2/32), and scoliosis (6/32) were observed. The clinical severity was not different between patients with EXT1 or EXT2 variants. One patient with an EXT2 variant and another with an EXT1 microdeletion had the most severe phenotype with class III disease. Four patients with no EXT1 or EXT2 variants had milder phenotypes. Intrafamilial variability in disease severity was not observed. CONCLUSION: We report a hereditary multiple osteochondroma cohort with clinical and molecular data including 12 novel intragenic variants in EXT1 or EXT2, and 4 microdeletions involving EXT1. Taken together, our data expand the existing knowledge of the phenotype-genotype spectrum in hereditary multiple osteochondroma.

Severe neurologic manifestations from cervical spine instability in spondylo-megaepiphyseal-metaphyseal dysplasia.

Spondylo-megaepiphyseal-metaphyseal dysplasia (SMMD; OMIM 613330) is a dysostosis/dysplasia caused by recessive mutations in the homeobox-containing gene, NKX3-2 (formerly known as BAPX1). Because of the rarity of the condition, its diagnostic features and natural course are not well known. We describe clinical and radiographic findings in six patients (five of which with homozygous mutations in the NKX3-2 gene) and highlight the unusual and severe changes in the cervical spine and the neurologic complications. In individuals with SMMD, the trunk and the neck are short, while the limbs, fingers and toes are disproportionately long. Radiographs show a severe ossification delay of the vertebral bodies with sagittal and coronal clefts, missing ossification of the pubic bones, large round "balloon-like" epiphyses of the long bones, and presence of multiple pseudoepiphyses at all metacarpals and phalanges. Reduced or absent ossification of the cervical vertebrae leads to cervical instability with anterior or posterior kinking of the cervical spine (swan neck-like deformity, kyknodysostosis). As a result of the cervical spine instability or deformation, five of six patients in our series suffered cervical cord injury that manifested clinically as limb spasticity. Although the number of individuals observed is small, the high incidence of cervical spine deformation in SMMD is unique among skeletal dysplasias. Early diagnosis of SMMD by recognition of the radiographic pattern might prevent of the neurologic complications via prophylactic cervical spine stabilization.

Homozygous inactivating mutations in the NKX3-2 gene result in spondylo-megaepiphyseal-metaphyseal dysplasia.

Spondylo-megaepiphyseal-metaphyseal dysplasia (SMMD) is a rare skeletal dysplasia with only a few cases reported in the literature. Affected individuals have a disproportionate short stature with a short and stiff neck and trunk. The limbs appear relatively long and may show flexion contractures of the distal joints. The most remarkable radiographic features are the delayed and impaired ossification of the vertebral bodies as well as the presence of large epiphyseal ossification centers and wide growth plates in the long tubular bones. Numerous pseudoepiphyses of the short tubular bones in hands and feet are another remarkable feature of the disorder. Genome wide homozygosity mapping followed by a candidate gene approach resulted in the elucidation of the genetic cause in three new consanguineous families with SMMD. Each proband was homozygous for a different inactivating mutation in NKX3-2, a homeobox-containing gene located on chromosome 4p15.33. Striking similarities were found when comparing the vertebral ossification defects in SMMD patients with those observed in the Nkx3-2 null mice. Distinguishing features were the asplenia found in the mutant mice and the radiographic abnormalities in the limbs only observed in SMMD patients. The absence of the latter anomalies in the murine model may be due to the perinatal death of the affected animals. This study illustrates that NKX3-2 plays an important role in endochondral ossification of both the axial and appendicular skeleton in humans. In addition, it defines SMMD as yet another skeletal dysplasia with autosomal-recessive inheritance and a distinct phenotype.

Evaluation of exonic copy numbers of SMN1 and SMN2 genes in SMA.

SMA is a neuromuscular disease and occurs primarily through autosomal recessive inheritance. Identification of deletions in the SMN1 gene especially in the exon 7 and exon 8 regions (hot spot), are used in carrier testing. The exact copy numbers of those exons in the SMN1 and SMN2 genes in 113 patients who presented with a pre-diagnosis of SMA were determined using MLPA method. We aimed to reveal both the most common copy number profiles of different SMA types. It was found that the frequency of homozygous deletions in SMN1 was 15.9%, while heterozygous deletions was 16.9%. The most common SMN-MLPA profile was 0-0-3-3. In the cases with homozygous deletion, SMA type III diagnosis was observed most frequently (44%), and the rate of consanguineous marriage was found 33%. Two cases with the same exonic copy number profile but with different clinical subtypes were identified in a family. We also detected distinct exonic deletion and duplication MLPA profiles for the first time. We created "the SMA signature" that can be added to patient reports. Furthermore, our data are important for revealing potential local profiles of SMA and describing the disease in genetic reports in a way that is clear and comprehensive.

Novel Gene Variants Associated with Primary Ciliary Dyskinesia.

OBJECTIVES: To determine the demographic, clinical, and genetic profile of Turkish Caucasian PCD cases. METHODS: Targeted next-generation sequencing (t-NGS) of 46 nuclear genes was performed in 21 unrelated PCD cases. Sanger sequencing confirmed of potentially disease-related variations, and genotype-phenotype correlations were evaluated. RESULTS: Disease-related variations were identified in eight different genes (CCDC39, CCDC40, CCDC151, DNAAF2, DNAAF4, DNAH11, HYDIN, RSPH4A) in 52.4% (11/21) of the cases. The frequency of variations for CCDC151, DNAH11, and DNAAF2 genes which were highly mutated genes in the cohort was 18% in 11 patients. Each of the remaining gene variations was detected once (9%) in different patients. The variants, p.R482fs*12 in CCDC151, p.E216* in DNAAF2, p.I317* in DNAAF4, p.L318P and p.R1865* in DNAH11, and p.N1505D and p.L1167P in HYDIN gene were identified as novel variations. Interestingly, varying phenotypic findings were identified even in patients with the same mutation, which once again confirmed that PCD has a high phenotypic heterogeneity and shows individual differences. CONCLUSION: This t-NGS panel is potentially helpful for exact and rapid identification of reported/novel PCD-disease-causing variants to establish the molecular diagnosis of ciliary diseases.