Genetic aspects of ataxias in a cohort of Turkish patients.

INTRODUCTION: Ataxia is one of the clinical findings of the movement disorder disease group. Although there are many underlying etiological reasons, genetic etiology has an increasing significance thanks to the recently developing technology. The aim of this study is to present the variants detected in WES analysis excluding non-genetic causes, in patients with ataxia. METHODS: Thirty-six patients who were referred to us with findings of ataxia and diagnosed through WES or other molecular genetic analysis methods were included in our study. At the same time, information such as the onset time of the complaints, consanguinity status between parents, and the presence of relatives with similar symptoms were evaluated. If available, the patient's biochemical and radiological test results were presented. RESULTS: Thirty-six patients were diagnosed through WES or CES. The rate of detected autosomal recessive inheritance disease was 80.5%, while that of autosomal dominant inheritance disease was 19.5%. Abnormal cerebellum was detected on brain MRI images in 26 patients, while polyneuropathy was detected on EMG in eleven of them. While the majority of the patients were compatible with similar cases reported in the literature, five patients had different/additional features (variants in MCM3AP, AGTPBP1, GDAP2, and SH3TC2 genes). CONCLUSIONS: The diagnosis of ataxia patients with unknown etiology is made possible thanks to these clues. Consideration of a genetic approach is recommended in patients with ataxia of unknown etiology.

Genetic and Clinical Approach To Microcephaly: A 5-Year Single Center Experience.

Microcephaly is a dysmorphic feature characterized by small head size more than two standard deviations below the mean for age, sex, and ethnicity. There are several etiological factors ranging from environmental toxins or infections to genetic disorders. We report clinical, radiological, and molecular genetic investigations of patients with microcephaly from a single center over 5-year period. There were 92 patients with a genetic diagnosis. Based on their genetic diagnosis, we grouped patients into three categories: (1) microcephaly with copy number variations (CNVs), (2) microcephaly with single gene disorders, and (3) microcephaly with aneuploidies. The most common category was aneuploidy in 59% of the patients, followed by single gene disorders in 23% of the patients and CNVs in 18% of the patients. We think that history and physical examination guide physicians to choose the most appropriate genetic testing to identify underlying diagnosis.

A female case of 5,10-methenyltetrahydrofolate synthetase deficiency with novel neuro-imaging abnormalities.

BACKGROUND: Folate metabolism disorders can affect various organ systems, including the nervous system. 5,10-methenyltetrahydrofolate synthetase deficiency is a rare cerebral folate deficiency in which MTHFS activity is disrupted with low-normal cerebrospinal fluid (CSF) 5,10-methenyltetrahydrofolate levels, while peripheral folate levels are normal. CASE REPORT: We present here a female patient with developmental delay, microcephaly, hypotonia, nystagmus, and seizure in which a distinct brain MRI and CT showed restricted diffusion in the bilateral parietal and occipital lobes, and calcifications of the bilateral putamen, globus pallidus, and caudate nucleus, and the bilateral parietal and occipital lobes. Laboratory tests revealed macrocytic anemia, increased homocysteine, low-normal CSF 5,10-methenyltetrahydrofolate, and low CSF folate, but normal serum vitamin B12 and folate levels. A whole exome sequencing analysis verified the diagnosis of 5,10-methenyltetrahydrofolate synthetase deficiency. CONCLUSIONS: We have added novel knowledge which is nystagmus and hypotonia in the clinical findings, the involvement and restriction of bilateral putamen, globus pallidus, parietal and occipital lobes, and calcification of the bilateral putamen, globus pallidus, caudate nucleus, and parietal and occipital lobes in neuroimaging images and also low CSF folate in the metabolic investigation with the patient in 5,10-methenyltetrahydrofolate synthetase deficiency.

High prevalence of multilocus pathogenic variation in neurodevelopmental disorders in the Turkish population.

Neurodevelopmental disorders (NDDs) are clinically and genetically heterogenous; many such disorders are secondary to perturbation in brain development and/or function. The prevalence of NDDs is > 3%, resulting in significant sociocultural and economic challenges to society. With recent advances in family-based genomics, rare-variant analyses, and further exploration of the Clan Genomics hypothesis, there has been a logarithmic explosion in neurogenetic "disease-associated genes" molecular etiology and biology of NDDs; however, the majority of NDDs remain molecularly undiagnosed. We applied genome-wide screening technologies, including exome sequencing (ES) and whole-genome sequencing (WGS), to identify the molecular etiology of 234 newly enrolled subjects and 20 previously unsolved Turkish NDD families. In 176 of the 234 studied families (75.2%), a plausible and genetically parsimonious molecular etiology was identified. Out of 176 solved families, deleterious variants were identified in 218 distinct genes, further documenting the enormous genetic heterogeneity and diverse perturbations in human biology underlying NDDs. We propose 86 candidate disease-trait-associated genes for an NDD phenotype. Importantly, on the basis of objective and internally established variant prioritization criteria, we identified 51 families (51/176 = 28.9%) with multilocus pathogenic variation (MPV), mostly driven by runs of homozygosity (ROHs) - reflecting genomic segments/haplotypes that are identical-by-descent. Furthermore, with the use of additional bioinformatic tools and expansion of ES to additional family members, we established a molecular diagnosis in 5 out of 20 families (25%) who remained undiagnosed in our previously studied NDD cohort emanating from Turkey.

Genotype to Phenotype: Identification of Mucopolysaccharidosis Type IIIB (Sanfilippo's B) Case Using Whole Exome Sequencing.

Mucopolysaccharidosis type IIIB (Sanfilippo's B; OMIM no.: 252920) is a lysosomal storage disorder caused by defective degradation of heparan sulfate. The enzyme that has decreased function in this disease is α-N acetylglucosaminidase. This enzyme is encoded by the NAGLU gene. A 9-year-old male patient was referred to us with speech disability, developmental delay, hepatomegaly, mild learning disability, and otitis media with effusion complaints. Whole exome sequencing (WES) was performed because of consanguinity between the parents of the patient and the lack of specific prediagnosis. As a result of the patient's WES analysis, a homozygous mutation was detected in the NAGLU gene. The leukocyte enzyme activity was then evaluated to confirm the diagnosis. Alpha-N acetylglucosaminidase deficiency was found. Alpha-N acetylglucosaminidase activity was 0.2 nmol/mLh. WES is a successful diagnostic method in the diagnosis of the mild clinical diseases with recessive inheritance. In addition, our case is a good example of genotype to phenotype diagnosis. Because in storage diseases, the diagnosis is made by leukocyte enzyme analysis first, and then the result is confirmed by gene analysis. The opposite situation occurred in our case.

Understanding What You Have Found: A Family With a Mutation in the LAMA1 Gene With Literature Review.

INTRODUCTION: Cerebellar dysplasia with cysts (CDC) is an imaging finding which is typically seen with in individuals with dystroglycanopathy. One of the diseases causing this condition is "Poretti-Boltshauser Syndrome; PTBHS" (OMIM #615960). Homozygous or compound heterozygous mutations in the LAMA1 gene cause this disease. CASE PRESENTATION: 7 years old twin siblings consulted to the medical genetics department because of walking problems and cerebellar examination findings. MANAGEMENT AND OUTCOME: Clinical and radiological findings of the patient suggested a syndrome with recessive inheritance. Whole exome sequencing (WES) test was performed for definitive diagnosis. As a result of the patient's WES analysis, a homozygous mutation was detected in the LAMA1 gene. DISCUSSION: When determining the inheritance pattern of genetic diseases, if parents have consanquinity, this situation leads us to recessive inheritance diseases. Even if we are not consanquinity, but they say the same village, it is necessary to pay attention to the diseases of the recessive group. Whole exome sequencing analysis results in large amount of data generation. A good clinical evaluation is required to detect the mutation as a result of large data. To understand what we have found, we need to know what we are looking for.

Success of Face Analysis Technology in Rare Genetic Diseases Diagnosed by Whole-Exome Sequencing: A Single-Center Experience.

The diagnosis of rare genetic diseases is one of the most difficult areas in medicine. Whole-exome sequencing (WES) technology makes it easier to diagnose these diseases. In addition, next-generation phenotyping can help to diagnose computer-based algorithms. Detailed dysmorphologic findings of 25 patients diagnosed by WES in our center were described. The success of this technology in diagnosing rare genetic diseases was investigated by scanning the photographs of 25 patients with Face2Gene application. The application listed possible preliminary diagnoses (30 disease suggestion). Of these, 12 (48%) cases were correctly matched. The most common disease group in the patients was neurological disease (96%). The most common mode of inheritance in the patients was autosomal recessive. The rate of consanguineous marriages was determined in 80% of the patients. Ten patients had microcephaly and 7 patients had corpus callosum anomaly. In our study, we found that the success of Face2Gene was lower than described in the literature. We think that the probable cause of this condition is that the cases are very rare, and there is not enough data about these diseases in the application. Therefore, it is recommended that applications should be used more frequently by pediatricians and clinical geneticists. The diagnosis of rare diseases still is quite difficult. Nowadays, WES is a successful method. However, applications such as Face2Gene help to make a clinical prediagnosis and create a larger database.

The Genomics of Arthrogryposis, a Complex Trait: Candidate Genes and Further Evidence for Oligogenic Inheritance.

Arthrogryposis is a clinical finding that is present either as a feature of a neuromuscular condition or as part of a systemic disease in over 400 Mendelian conditions. The underlying molecular etiology remains largely unknown because of genetic and phenotypic heterogeneity. We applied exome sequencing (ES) in a cohort of 89 families with the clinical sign of arthrogryposis. Additional molecular techniques including array comparative genomic hybridization (aCGH) and Droplet Digital PCR (ddPCR) were performed on individuals who were found to have pathogenic copy number variants (CNVs) and mosaicism, respectively. A molecular diagnosis was established in 65.2% (58/89) of families. Eleven out of 58 families (19.0%) showed evidence for potential involvement of pathogenic variation at more than one locus, probably driven by absence of heterozygosity (AOH) burden due to identity-by-descent (IBD). RYR3, MYOM2, ERGIC1, SPTBN4, and ABCA7 represent genes, identified in two or more families, for which mutations are probably causative for arthrogryposis. We also provide evidence for the involvement of CNVs in the etiology of arthrogryposis and for the idea that both mono-allelic and bi-allelic variants in the same gene cause either similar or distinct syndromes. We were able to identify the molecular etiology in nine out of 20 families who underwent reanalysis. In summary, our data from family-based ES further delineate the molecular etiology of arthrogryposis, yielded several candidate disease-associated genes, and provide evidence for mutational burden in a biological pathway or network. Our study also highlights the importance of reanalysis of individuals with unsolved diagnoses in conjunction with sequencing extended family members.

Analysis of musculoskeletal dysmorphic abnormalities of 20 fetuses.

OBJECTIVES: This study aims to report rates of skeletal abnormalities and their risk factors in light of information obtained in a fetal autopsy series. PATIENTS AND METHODS: The study included 20 fetuses (11 males, 8 females and 1 ambiguous genitalia; mean age 19.3±4.0 weeks; range 16 to 32 week) who underwent autopsy in our hospital between January 2013 and March 2015. Fetuses were systematically classified according to age, gender, family history, abortus week, abortus type, and extremity and organ abnormalities. Skin biopsies were performed for genetic evaluation. Radiographic, pathologic and genetic findings were classified. RESULTS: Except one spontaneous abortus, all cases were applied medical abortus (94.1%). Genetic diagnosis could not be established in seven cases, whereas genetic disorders were identified in 13 cases: two trisomy 13, two trisomy 18, one (triploidi) 69,XXY, two arthrogryposis multiplex congenita, one osteogenesis imperfecta, one lethal multiple pterygium, one Saldino-Noonan syndrome, one teratogenic drug effect, one perinatal lethal hypophosphatasia, and one Beckwith-Wiedemann syndrome. Decreased fetal movement was one of the most frequently observed findings. Consanguineous marriage, oligohydramnios, drug addiction of the mother, teratogenic exposure, and other systemic abnormalities were risk factors. CONCLUSION: Skeletal dysplasias are rare diseases. Clinicians should be careful for skeletal abnormalities in perinatal period follow-ups.

Infantile Type Sandhoff Disease with Striking Brain MRI Findings and a Novel Mutation.

BACKGROUND: Sandhoff disease is an autosomal recessive disorder caused by ß-hexosaminidase deficiency in which the ganglioside GM2 and other glycolipids accumulate intracellularly within lysosomes. This process results in progressive motor neuron manifestations, death from respiratory failure and infections in infantiles. CASE REPORT: This report presents a 22-month-old girl with infantile type Sandhoff disease that was hospitalized for generalized seizures and psychomotor retardation. She was diagnosed with a genetically proven novel mutation and by demonstrating it's specific imaging findings. CONCLUSIONS: Determination of spesific changes in neuroimaging which are initial findings for GM2 gangliosidosis is important from the point of diagnosis and follow-up in infants suspected of having a neurodegenerative disease.

A rare case of 3C disease: Ritscher-Schinzel syndrome presenting with recurrent talipes equinovarus.

INTRODUCTION: Club foot (CF) is characterized by multiple deformities such as varus, adductus and internal rotation of the forefoot. It is well-known and a frequent congenital disorder. CF can concurrently be seen with several diseases but it can rarely manifest as a component of any other syndrome. Ritscher-Schinzel syndrome, or cranio-cerebello-cardiac syndrome, is rarely seen and has autosomal recessive inheritance. It is characterized by cranio-facial, cerebellar and cardiac abnormalities. We report a case diagnosed as Ritscher-Schinzel syndrome concurrent with persistent CF. PRESENTATION OF CASE: A two-year-old boy with persistent CF and concurrent congenital hip dysplasia. Despite successful serial casting and subsequent achilloplasty a clinical relapse was observed in our patient. After a detailed phenotypic evaluation, genetical tests and imaging technique the patient was diagnosed 3C Ritscher-Schinzel syndrome. DISCUSSION: A comprehensive literature review did not show any reports about concurrent hip dysplasia and clubfoot in Ritscher-Schinzel syndrome. We report that CF may be associated with rare genetical abnormalities. CONCLUSION: With this report we would like to raise awareness about the possible association of persistent CF with this rare genetical disorder, Ritscher-Schinzel syndrome. It should be included in differential diagnosis of patients with persistent CF.

46,XX, der(15),t(Y;15)(q12;p11) karyotype in an azoospermic male.

We report on a Yq/15p translocation in a 23-year-old infertile male referred for Klinefelter Syndrome testing, who had azoospermia and bilateral small testes. Hormonal studies revealed hypergonadotropic hypogonadism. Conventional cytogenetic procedures giemsa trypsin giemsa (GTG) and high resolution banding (HRB) and molecular cytogenetic techniques Fluorescence In Situ Hybridization (FISH) performed on high-resolution lymphocyte chromosomes revealed the karyotype 46,XX, t(Y;15)(q12;p11). SRY-gene was confirmed to be present by classical Polymerase Chain Reaction (PCR) methods. His father carried de novo derivative chromosome 15 [45,X, t(Y;15)(q12;p11)] and was fertile; the karyotype of the father using G-band technique confirmed a reciprocal balanced translocation between chromosome Y and 15. In the proband, the der (15) has been inherited from the father because the mother had a normal karyotype (46,XX). In the proband, the der (15) could have produced genetic imbalance leading to unbalanced robertson translocation between chromosome Y and 15, which might have resulted in azoospermia and infertility in the proband. The paternal translocation might have lead to formation of imbalanced ova, which might be resulted infertility in the proband. Sister's karyotypes was normal (46,XX) while his brother was not analyzed.