Voltage-gated sodium channel epilepsies in a tertiary care center: Phenotypic spectrum with correlation to predicted functional effects.

BACKGROUND: Variants in sodium channel genes (SCN) are strongly associated with epilepsy phenotypes. Our aim in this study to evaluate the genotype and phenotype correlation of patients with SCN variants in our tertiary care center. METHODS: In this retrospective study, patients with SCN variants and epilepsy who were followed up at our clinic between 2018 and 2022 were evaluated. Our study discussed the demographics of the patients, the seizure types, the age of seizure onset, the SCN variants, the domains and the functions of the variants, the magnetic resonance imaging findings, the motor, cognitive, and psychiatric comorbidities, and the response to anti-seizure medication. Genetic testing was conducted using a next-generation sequencing gene panel (epilepsy panel) or a whole-exome sequencing. For evaluating variant function, we used a prediction tool (https://funnc.shinyapps.io/shinyappweb/ site). To assess protein domains, we used the PER viewer (http://per.broadinstitute.org/). RESULTS: Twenty-three patients with SCN variants and epilepsy have been identified. Sixteen patients had variants in the SCN1A, six patients had variants in the SCN2A, and one patient had a variant in the SCN3A. Two novel SCN1A variants and two novel SCN2A variants were identified. The analysis revealed 14/23 missense, 6/23 nonsense, 2/23 frameshift, and 1/23 splice site variants in the SCN. There are seven variants predicted to be gain-of-function and 13 predicted to be loss-of-function. Among 23 patients; 11 had Dravet Syndrome, 6 had early infantile developmental and epileptic encephalopathy, three had genetic epilepsy with febrile seizures plus spectrum disorder, one had self-limited familial neonatal-infantile epilepsy, one had self-limited infantile epilepsy and one had infantile childhood development epileptic encephalopathy. CONCLUSION: Our cohort consists of mainly SCN1 variants, most of them were predicted to be loss of function. Dravet syndrome was the most common phenotype. The prediction tool used in our study demonstrated overall compatibility with clinical findings. Due to the diverse clinical manifestations of variant functions, it may assist in guiding medication selection and predicting outcomes. We believe that such a tool will help the clinician in both prognosis prediction and solving therapeutic challenges in this group where refractory seizures are common.

A Rare Inherited Bone Marrow Failure Syndrome Disclosed by Reanalysis of the Exome Data of a Patient Evaluated for Cytopenia and Dysmorphic Features.

BACKGROUND: Multisystemic findings of inherited bone marrow failure syndromes may cause difficulty in diagnosis. Exome sequencing (ES) helps to define the etiology of rare diseases and reanalysis offers a valuable new diagnostic approach. Herein, we present the clinical and molecular characteristics of a girl who was referred for cytopenia and frequent infections. CASE REPORT: A 5-year-old girl with cytopenia, dysmorphism, short stature, developmental delay, and myopia was referred for genetic counseling. Reanalysis of the ES data revealed a homozygous splice-site variant in the DNAJC21 (NM_001012339.3:c.983+1G>A), causing Shwachman-Diamond Syndrome (SDS). It was shown by the RNA sequencing that exon 7 was skipped, causing an 88-nucleotide deletion. CONCLUSIONS: Precise genetic diagnosis enables genetic counseling and improves patient management by avoiding inappropriate treatment and unnecessary testing. This report would contribute to the clinical and molecular understanding of this rare type of SDS caused by DNAJC21 variants and expand the phenotypic features of this condition.

A rare multisystemic disorder with chronic kidney disease: Karyomegalic interstitial nephritis due to homozygous FAN1 c.2260C>T variant.

Karyomegalic interstitial nephritis (KIN) is a rare entity associated with biallelic FAN1 (FANCD2/FANCI-Associated Nuclease 1) gene variants. In FAN1-related KIN, abnormal liver function tests and respiratory involvement are common, in addition to chronic kidney disease. Karyomegalic changes have also been reported in many other organs in patients with FAN1-related KIN in various studies. We report the case of a 35-year-old male with chronic kidney disease of unknown aetiology, concurrent recurrent upper and lower respiratory tract infections, and elevated liver function test results with unidentified aetiology. The patient's family history was remarkable for consanguineous parent marriage and history of kidney transplantation in his aunt. A kidney biopsy was performed, which was consistent with KIN. Clinical exome sequencing revealed a homozygous nonsense variant NM_014967.5 (FAN1): c. 2260C > T (p.Arg754Ter). According to the American College of Medical Genetics (ACMG) criteria, this variant is pathogenic and, to the best of our knowledge, has not been previously reported, homozygously. Therefore, the histopathological and clinical diagnoses of KIN were confirmed by genetic studies in our patient. This case report expands the genetic spectrum of FAN1-related KIN, and briefly reviews the current literature data.

De Novo and Bi-allelic Pathogenic Variants in NARS1 Cause Neurodevelopmental Delay Due to Toxic Gain-of-Function and Partial Loss-of-Function Effects.

Aminoacyl-tRNA synthetases (ARSs) are ubiquitous, ancient enzymes that charge amino acids to cognate tRNA molecules, the essential first step of protein translation. Here, we describe 32 individuals from 21 families, presenting with microcephaly, neurodevelopmental delay, seizures, peripheral neuropathy, and ataxia, with de novo heterozygous and bi-allelic mutations in asparaginyl-tRNA synthetase (NARS1). We demonstrate a reduction in NARS1 mRNA expression as well as in NARS1 enzyme levels and activity in both individual fibroblasts and induced neural progenitor cells (iNPCs). Molecular modeling of the recessive c.1633C>T (p.Arg545Cys) variant shows weaker spatial positioning and tRNA selectivity. We conclude that de novo and bi-allelic mutations in NARS1 are a significant cause of neurodevelopmental disease, where the mechanism for de novo variants could be toxic gain-of-function and for recessive variants, partial loss-of-function.

An investigation of the etiology and follow-up findings in 35 children with overgrowth syndromes, including biallelic SUZ12 variant.

Overgrowth-intellectual disability (OGID) syndromes are clinically and genetically heterogeneous group of disorders. The aim of this study was to examine the molecular etiology and long-term follow-up findings of Turkish OGID cohort. Thirty-five children with OGID were included in the study. Single gene sequencing, clinical exome analysis, chromosomal microarray analysis and whole exome sequencing were performed. Five pathogenic copy number variants were detected in the patients; three of them located on chromosome 5q35.2 (encompassing NSD1), others on 9q22.3 and 22q13.31. In 19 of 35 patients; we identified pathogenic variants in OGID genes associated with epigenetic regulation, NSD1 (n = 15), HIST1H1E (n = 1), SETD1B (n = 1), and SUZ12 (n = 2). The pathogenic variants in PIK3CA (n = 2), ABCC9 (n = 1), GPC4 (n = 2), FIBP (n = 1), and TMEM94 (n = 1) which had a role in other growth pathways were detected in seven patients. The diagnostic yield was 31/35(88%). Twelve pathogenic variants were novel. The common facial feature of the patients was prominent forehead. The patients with Sotos syndrome were observed to have milder intellectual disability than patients with other OGID syndromes. In conclusion, this study showed, for the first time, that biallelic variants of SUZ12 caused Imagawa-Matsumoto syndrome, monoallelic variants in SETDIB resulted in OGID. Besides expanded the phenotypes of very rare OGID syndromes caused by FIBP and TMEM94.

Functional characterization of KCNMA1 mutation associated with dyskinesia, seizure, developmental delay, and cerebellar atrophy.

KCNMA1 located on chromosome 10q22.3, encodes the pore-forming α subunit of the 'Big K+' (BK) large conductance calcium and voltage-activated K + channel. Numerous evidence suggests the functional BK channel alterations produced by different KCNMA1 alleles may associate with different symptoms, such as paroxysmal non kinesigenic dyskinesia with gain of function and ataxia with loss of function. Functional classifications revealed two major patterns, gain of function and loss of function effects on channel properties in different cell lines. In the literature, two mutations have been shown to confer gain of function properties to BK channels: D434G and N995S. In this study, we report the functional characterization of a variant which was previously reported the whole exome sequencing revealed bi-allelic nonsense variation of the cytoplasmic domain of calcium-activated potassium channel subunit alpha-1 protein. To detect functional consequences of the variation, we parallely conducted two independent approaches. One is immunostaining using and the other one is electrophysiological recording using patch-clamp on wild-type and R458X mutant cells to detect the differences between wild-type and the mutant cells. We detected the gain of function effect for the mutation (NM_001161352.1 (ENST00000286628.8):c.1372C > T;Arg458*) using two parallel approaches. According to the result we found, the reported mutation causes the loss of function in the cell. It should be noted that in future studies, it can be thought that the functions of genes associated with channelopathies may have a dual effect such as loss and gain.

Biallelic loss of TRAPPC9 function links vesicle trafficking pathway to autosomal recessive intellectual disability.

BACKGROUND: The trafficking protein particle (TRAPP) complex subunit 9 (C9) protein is a member of TRAPP-II complexes and regulates vesicle trafficking. Biallelic mutations in the TRAPPC9 gene are responsible for intellectual disability with expanded developmental delay, epilepsy, microcephaly, and brain atrophy. TRAPPC9-related disease list is still expanding, however, the functional effects of only a limited fraction of these have been studied. METHODS: In a patient with a pathological variant in TRAPPC9, clinical examination and cranial imaging findings were evaluated. Whole-exome sequencing, followed by Sanger sequencing was performed to detect and verify the variant. To confirm the functional effect of the mutation; variant mRNA and protein expression levels were evaluated by qRT-PCR and Western blotting. Immunostaining for TRAPPC9 and lipid droplet accumulation were examined. RESULTS: We have identified a novel homozygous c.696C>G (p.Phe232Leu) pathogenic variant in TRAPPC9 (NM_031466.6) gene as a cause of severe developmental delay. Functional characterization of the TRAPPC9 variant resulted in decreased mRNA and protein expression. The intracellular findings showed that TRAPPC9 protein build-up around the nucleus in mutant type while there was no specific accumulation in the control cell line. This disrupted protein pattern affected the amount of neutral lipid-carrying vesicles and their homogenous distribution at a decreasing level. CONCLUSION: Biallelic variants in the TRAPPC9 gene have been reported as the underlying cause of intellectual disability. This study provides functional evidence of the novel variant in TRAPPC9 We demonstrated that the loss of function variant exclusively targeting TRAPPC9 may explicate the neurological findings through vesicle trafficking.

Expanding Clinical Phenotype of TRAPPC12-Related Childhood Encephalopathy: Two Cases and Review of Literature.

Biallelic mutations in the TRAPPC12 gene are responsible for early-onset progressive encephalopathy with brain atrophy and spasticity (PEBAS). To date, three different allelic variants have been reported. Next-generation sequencing allowed discovery of unique alternations in this gene with different phenotypes. We report two patients carrying TRAPPC12 variants, one previously reported and one unknown mutation, with severe neurodevelopmental delay and brain atrophy. Standard clinical examination and cranial imaging studies were performed in these two unrelated patients. In addition, whole-exome sequencing was performed, followed by Sanger sequencing for verification. The first patient, a 2-year-old boy, was found to be homozygous for the previously reported c.1880C > T (p.Ala627Val) mutation. He presented with a phenotype including severe progressive cortical atrophy, moderate cerebellar atrophy, epilepsy, and microcephaly, very similar to the previously reported cases. The second case, a 9-year-old boy, carried a novel homozygous c.679T > G (p.Phe227Val) variant and presented with mild cortical atrophy, severe cerebellar atrophy, and neither clinically manifest epilepsy nor microcephaly, which were previously considered typical findings in PEBAS with TRAPPC12 mutations. Our findings suggest that clinical and brain imaging findings might be more variable than previously anticipated; however, a larger number of observations would benefit for broader phenotypic spectrum.

Homozygous mutation in NUP107 leads to microcephaly with steroid-resistant nephrotic condition similar to Galloway-Mowat syndrome.

BACKGROUND: Microcephaly with nephrotic syndrome is a rare co-occurrence, constituting the Galloway-Mowat syndrome (GAMOS), caused by mutations in WDR73 (OMIM: 616144). However, not all patients harbour demonstrable WDR73 deleterious variants, suggesting that there are other yet unidentified factors contributing to GAMOS aetiology. METHODS: Autozygosity mapping and candidate analysis was used to identify deleterious variants in consanguineous families. Analysis of patient fibroblasts was used to study splicing and alterations in cellular function. RESULTS: In two consanguineous families with five affected individuals from Turkey with a GAMOS-like presentation, we identified a shared homozygous variant leading to partial exon 4 skipping in nucleoporin, 107-KD (NUP107). The founder mutation was associated with concomitant reduction in NUP107 protein and in the obligate binding partner NUP133 protein, as well as density of nuclear pores in patient cells. CONCLUSION: Recently, NUP107 was suggested as a candidate in a family with nephrotic syndrome and developmental delay. Other NUP107-reported cases had isolated renal phenotypes. With the addition of these individuals, we implicate an allele-specific critical role for NUP107 in the regulation of brain growth and a GAMOS-like presentation.

A multidisciplinary clinical approach to facioscapulohumeral muscular dystrophy.

BACKGROUND AND PURPOSE: Impaired shoulder function is the most disabling problem for daily life of Fascioscapulohumeral muscular dystrophy (FSHD) patients. Scapulothoracic arthrodesis can give a high impact to the functionality of patients. Here we report our experience with scapulothoracic arthrodesis and spinal stenosis surgery in FSHD patients. METHODS: 32 FSHD patients were collected between 2015-2016. Demographical and clinical features were documented. All the patients were neurologically examined. The Medical Research Council (MRC) and the FSHD evaluation scale was used to assess muscle involvement1. Scapulothoracic arthrodesis and spinal stenosis surgeries were performed in eligible patients. RESULTS: There were 16 male and 16 female (mean age 34.4 years; range 12-73) patients. 6 shoulders of 4 patients aged between 2132 years underwent scapulothoracic arthrodesis (two bilateral, one left and one right sided). Only one 63 years old female patient with severe hyperlordosis had spinal fusion surgery. All of the patients undergoing these corrective surgeries have better functionality in daily life, as well as superior shoulder elevation. CONCLUSION: Until the emergence and clinical use of novel therapeutics, surgical interventions are indicated in carefully selected patients with FSHD to improve arm movements, the posture and the quality of life of patients in general. Scapulothorosic arthrodesis is a management with good clinical results and patient satisfaction. In selected cases other corrective orthopedic surgeries like spinal fusion may also be considered.

Newly described clinical features in two siblings with MACS syndrome and a novel mutation in RIN2.

The disorder comprising Macrocephaly, Alopecia, Cutis laxa, and Scoliosis has been designated MACS syndrome. It is a rare condition, inherited in an autosomal recessive pattern. Three families from different ethnic origins have so far been reported and were all linked to homozygous mutations in RIN2, a gene encoding the Ras and Rab interactor 2 protein involved in cell trafficking. We describe herein the fourth family with MACS syndrome in two siblings carrying a novel homozygous mutation, c.1878_1879insC in exon 8 of the RIN2 gene, which predicts p.Ile627Hisfs*7. We also report on additional findings not previously described in MACS syndrome, including bronchiectasis and hypergonadotropic hypogonadism. Finally, our overall data support the argument that RIN2 syndrome is a more appropriate name for the disorder.

Long-Term Disease Course of Pontocerebellar Hypoplasia Type 10.

BACKGROUND: Pontocerebellar hypoplasia type 10 (PCH10) due to CLP1 gene mutations is characterized by structural brain anomalies, progressive microcephaly, severe intellectual and physical disabilities, and spasticity. In this follow-up study, evolution of phenotypic and neurological characteristics of patients with PCH10 is discussed. METHODS: Phenotype, growth parameters, motor functions, developmental tests, spasticity assessments, functional independence assessments, electroencephalography (EEG), and brain magnetic resonance imaging (MRI) of 10 patients with PCH10 were monitored on separate examinations. Alterations were recorded. RESULTS: Patients were followed-up for an average of 2.83 years. The tone of the upper extremities was significantly higher than that of the lower extremities, according to Modified Ashworth Scale (MAS) values. Sixty percent of patients could sit unsupported; 20% achieved supported sitting initially but lost the ability during follow-up. Absence of grabbing or sitting was observed in 20% of patients. During follow-up, one person achieved supported sitting and one person achieved head holding. Only one patient was able to speak a few words. Cerebellar atrophy (two of 10), pons hypoplasia (four of 10), cortical atrophy (seven of 10), enlarged ventricles (10 of 10), thinning of the corpus callosum (10 of 10), hypomyelination (six of 10), and increased white matter signal intensity (six of 10) were the observed MRI findings. CONCLUSIONS: Progressive cerebral and cerebellar atrophy was demonstrated radiologically for the first time in a PCH10 cohort. It is of crucial importance to identify these patients promptly with the help of dysmorphic findings and spasticity being pronounced in the upper extremities. Furthermore, we note that phenotypic and neurological examination findings tend to change slightly over time.

Phenotype-Genotype Correlations of GH1 Gene Variants in Patients with Isolated Growth Hormone Deficiency or Multiple Pituitary Hormone Deficiency.

INTRODUCTION: Genetic forms of growth hormone deficiency (GHD) may occur as isolated GHD (IGHD) or as a component of multiple pituitary hormone deficiency (MPHD). This study aimed to present the clinical and molecular characteristics of patients with IGHD/MPHD due to the GH1 gene variants. METHODS: A gene panel accommodating 25 genes associated with MPHD and short stature was used to search for small sequence variants. Multiplex ligation-dependent probe amplification was performed in patients with normal panel results to investigate gross deletion/duplications. Segregation in the family was performed by Sanger sequencing. RESULTS: The GH1 gene variants were detected in 5 patients from four unrelated families. One patient had IGHD IA due to homozygous whole GH1 gene deletion and one had IGHD IB due to novel homozygous c.162C>G/p.(Tyr54*) variant. Two patients from a family had previously reported heterozygous c.291+1G>A/p.(?) variant in which clinical and genetic characteristics were compatible with IGHD II accompanying MPHD. One patient had clinical and laboratory characteristics of IGHD II with MPHD but the heterozygous c.468 C>T/p.(R160W) variant had conflicting results about the relationship with the phenotype. CONCLUSION: Expanding our knowledge of the spectrum of GH1 gene variants by apprehending clinical and molecular data of more cases, helps to identify the genotype-phenotype correlation of IGHD/MPHD and the GH1 gene variants. These patients must be regularly followed up for the occurrence of additional pituitary hormone deficiencies.

A Novel RNPC3 Gene Variant Expands the Phenotype in Patients with Congenital Hypopituitarism and Neuropathy.

INTRODUCTION: Pathogenic biallelic RNPC3 variants cause congenital hypopituitarism (CH) with congenital cataracts, neuropathy, developmental delay/intellectual disability, primary ovarian insufficiency, and pituitary hypoplasia. Here, we aimed to evaluate the clinical and molecular characteristics of 2 patients with CH and neuropathy. MATERIALS AND METHODS: Proband was evaluated by clinical, laboratory, and radiological exams, followed by exome sequencing (ES). Clinical investigation of an affected sibling and variant segregation in the family was performed by Sanger sequencing. A three-dimensional protein model study was conducted to predict the effect of the variant on the function of the RNPC3 peptide. RESULTS: Proband was a 16-month-old girl who was referred for the evaluation of failure to thrive. Her height, weight, and head circumference were 55.8 cm (-7.6 SDS), 6.5 kg (-3.6 SDS), and 41.8 cm (-3.82), respectively. She had a developmental delay and intellectual disability. Central hypothyroidism, growth hormone, and prolactin deficiencies were identified, and MRI revealed pituitary hypoplasia. Electroneuromyography performed for the gait abnormality revealed peripheral neuropathy. A homozygous novel variant c.484C>T/p.(Pro162Ser) in the RNPC3 was detected in the ES. Her brother had the same genotype, and he similarly had pituitary hormone deficiencies with polyneuropathy. CONCLUSION: Expanding our knowledge of the spectrum of RNPC3 variants, and apprehending clinical and molecular data of additional cases, is decisive for accurate diagnosis and genetic counseling.

Gonadoblastoma with Dysgerminoma in a Virilized Adolescent with Karyotype 46,XX: A Case Report and Review of the Literature.

Gonadoblastoma is a rare ovarian tumor composed of sex cord cells and primitive germ cells. While the majority of gonadoblastomas are found in individuals with 46,XY gonadal dysgenesis, they are also rarely seen in patients with a 46,XX karyotype. We report a case of a fourteen-year-and-six-month-old girl presenting with an uncommon cause of virilization due to a virilizing ovarian tumor. The patient underwent bilateral salpingo-oophorectomy. Upon histopathological examination, the excised tumor was confirmed to be bilateral gonadoblastoma, with dysgerminoma on the left side. Malignant gonadal tumors should be considered in cases of primary gonadal insufficiency with a 46,XX karyotype and progressive virilization. Even when laboratory and imaging tests show no abnormalities, a gonadal biopsy should be considered.

LRP4 mutations alter Wnt/beta-catenin signaling and cause limb and kidney malformations in Cenani-Lenz syndrome.

Cenani-Lenz syndrome (CLS) is an autosomal-recessive congenital disorder affecting distal limb development. It is characterized mainly by syndactyly and/or oligodactyly and is now shown to be commonly associated with kidney anomalies. We used a homozygosity-mapping approach to map the CLS1 locus to chromosome 11p11.2-q13.1. By sequencing candidate genes, we identified recessive LRP4 mutations in 12 families with CLS. LRP4 belongs to the low-density lipoprotein (LDL) receptor-related proteins (LRPs), which are essential for various developmental processes. LRP4 is known to antagonize LRP6-mediated activation of canonical Wnt signaling, a function that is lost by the identified mutations. Our findings increase the spectrum of congenital anomalies associated with abnormal lipoprotein receptor-dependent signaling.

A Second Family with Myhre Syndrome Caused by the Same Recurrent SMAD4 Pathogenic Variation (p.Arg496Cys).

Introduction: Myhre syndrome (MS; OMIM #139210) is a rare connective tissue disorder presenting with cardiovascular, respiratory, gastrointestinal, and skeletal system findings. Fewer than 100 patients were reported until recently, and all molecularly confirmed cases had de novo heterozygous gain-of-function mutations in the SMAD4 gene. Dysregulation of the TGF-beta signaling pathway leads to axial and appendicular skeleton, connective tissue, cardiovascular system, and central nervous system abnormalities. Case Presentation: Two siblings, 12 and 9 years old, were referred to us because of intellectual disability, neurodevelopmental delay, and dysmorphic facial features. Physical examination revealed hypertelorism, strabismus, small mouth, prognathism, short neck, stiff skin, and brachydactyly. Discussion: With a clinical diagnosis of MS, the SMAD4 gene was analyzed via Sanger sequencing, and a heterozygous c.1486C>T (p.Arg496Cys) pathogenic variation was detected in both of the siblings. The segregation analysis revealed that the mutation was inherited from the father who displayed a milder phenotype. Among the 90 patients in the literature, one family was reported in which two siblings carried the same variation (p.Arg496Cys), inherited from the severely affected mother. We are reporting the second family which has three affected family members, a father and two children. We report this study to remind the clinicians to be aware of the parental transmission of SMAD4 variations and also evaluate the parents of the Myhre cases.

Clinical and bi-genomic DNA findings of patients suspected to have mitochondrial diseases.

Background: Mitochondrial diseases are the most common group of inherited metabolic disorders, causing difficulties in definite diagnosis due to clinical and genetic heterogeneity. Clinical components are predominantly associated with pathogenic variants shown in nuclear or mitochondrial genomes that affect vital respiratory chain function. The development of high-throughput sequencing technologies has accelerated the elucidation of the genetic etiology of many genetic diseases that previously remained undiagnosed. Methods: Thirty affected patients from 24 unrelated families with clinical, radiological, biochemical, and histopathological evaluations considered for mitochondrial diseases were investigated. DNA isolated from the peripheral blood samples of probands was sequenced for nuclear exome and mitochondrial DNA (mtDNA) analyses. MtDNA sequencing was also performed from the muscle biopsy material in one patient. For segregation, Sanger sequencing is performed for pathogenic alterations in five other affected family members and healthy parents. Results: Exome sequencing revealed 14 different pathogenic variants in nine genes encoding mitochondrial function peptides (AARS2, EARS2, ECHS1, FBXL4, MICOS13, NDUFAF6, OXCT1, POLG, and TK2) in 12 patients from nine families and four variants in genes encoding important for muscle structure (CAPN3, DYSF, and TCAP) in six patients from four families. Three probands carried pathogenic mtDNA variations in two genes (MT-ATP6 and MT-TL1). Nine variants in five genes are reported for the first time with disease association: (AARS2: c.277C>T/p.(R93*), c.845C>G/p.(S282C); EARS2: c.319C>T/p.(R107C), c.1283delC/p.(P428Lfs*); ECHS1: c.161G>A/p.(R54His); c.202G>A/p.(E68Lys); NDUFAF6: c.479delA/p.(N162Ifs*27); and OXCT1: c.1370C>T/p.(T457I), c.1173-139G>T/p.(?). Conclusion: Bi-genomic DNA sequencing clarified genetic etiology in 67% (16/24) of the families. Diagnostic utility by mtDNA sequencing in 13% (3/24) and exome sequencing in 54% (13/24) of the families prioritized searching for nuclear genome pathologies for the first-tier test. Weakness and muscle wasting observed in 17% (4/24) of the families underlined that limb-girdle muscular dystrophy, similar to mitochondrial myopathy, is an essential point for differential diagnosis. The correct diagnosis is crucial for comprehensive genetic counseling of families. Also, it contributes to making treatment-helpful referrals, such as ensuring early access to medication for patients with mutations in the TK2 gene.

A Novel Mutation in the TRIP11 Gene: Diagnostic Approach from Relatively Common Skeletal Dysplasias to an Extremely Rare Odontochondrodysplasia

Odontochondrodysplasia (ODCD, OMIM #184260) is a rare, non-lethal skeletal dysplasia characterized by involvement of the spine and metaphyseal regions of the long bones, pulmonary hypoplasia, short stature, joint hypermobility, and dentinogenesis imperfecta. ODCD is inherited in an autosomal recessive fashion with an unknown frequency caused by mutations of the thyroid hormone receptor interactor 11 gene (TRIP11; OMIM *604505). The TRIP11 gene encodes the Golgi microtubule-associated protein 210 (GMAP-210), which is an indispensable protein for the function of the Golgi apparatus. Mutations in TRIP11 also cause achondrogenesis type 1A (ACG1A). Null mutations of TRIP11 lead to ACG1A, also known as a lethal skeletal dysplasia, while hypomorphic mutations cause ODCD. Here we report a male child diagnosed as ODCD with a novel compound heterozygous mutation who presented with skeletal changes, short stature, dentinogenesis imperfecta, and facial dysmorphism resembling achondroplasia and hypochondroplasia.

Clinical and molecular findings in 6 Turkish cases with Krabbe disease.

BACKGROUND: Krabbe disease is a rare lysosomal storage disorder with a neurodegenerative course that occurs because of the deficiency of the beta-galactocerebrosidase (GALC) enzyme activity. The genetic basis of Krabbe disease consists of biallelic mutations in the GALC gene, but the genetic spectrum in the Turkish population is poorly defined. We aimed to present a Turkish case-series with infantile-onset Krabbe disease, define the clinical and molecular findings and compare the genetic spectrum with the mutations previously reported in the literature. METHODS: Six cases, who were referred to our clinic between 2015-2019, with a definite diagnosis of infantileonset Krabbe disease were included in the study. The family history, clinical information, biochemical and radiological examinations of the patients were screened and evaluated. All encoded exons and exon-intron regions of the GALC gene were sequenced using next generation sequencing technology. Multiplex ligationdependent probe amplification analysis was used for deletion type mutations that could not be detected by sequence analysis. RESULTS: GALC gene sequence analysis revealed four known mutations including c.1394C > T (p.Thr465Ile), c.411_413delTAA (p.Lys139del), c.820G > C (p.Glu274Gln), and 30 kilobase deletion mutation among the exons 11-17 (IVS10del30kbp). Moreover, the c.1623G > A (p.Trp541Ter) variant, which was not previously reported in the literature, was detected in two cases. CONCLUSIONS: We believe that the demonstration of the genetic spectrum of infantile-onset Krabbe disease in Turkish patients will be an important contribution to the GALC mutation data in our country. More importantly, two novel variants were defined. This knowledge may enable early detection and treatment with the advent of a carrier or newborn screening tests.