Expanding the clinical and genetic landscape of (developmental) epileptic encephalopathy with spike-and-wave activation in sleep: results from studies of a Turkish cohort.

The terms developmental epileptic encephalopathy with spike-and-wave activation in sleep (DEE-SWAS) and epileptic encephalopathy with spike-and-wave activation in sleep (EE-SWAS) designate a spectrum of conditions that are typified by different combinations of motor, cognitive, language, and behavioral regression linked to robust spike-and-wave activity during sleep. In this study, we aimed at describing the clinical and molecular findings in "(developmental) epileptic encephalopathy with spike-and-wave activation in sleep" (D)EE-SWAS) patients as well as at contributing to the genetic etiologic spectrum of (D)EE-SWAS. Single nucleotide polymorphism (SNP) array and whole-exome sequencing (WES) techniques were used to determine the underlying genetic etiologies. Of the 24 patients included in the study, 8 (33%) were female and 16 (67%) were male. The median age at onset of the first seizure was 4 years and the median age at diagnosis of (D)EE-SWAS was 5 years. Of the 24 cases included in the study, 13 were compatible with the clinical diagnosis of DEE-SWAS and 11 were compatible with the clinical diagnosis of EE-SWAS. Abnormal perinatal history was present in four cases (17%), and two cases (8%) had a family history of epilepsy. Approximately two-thirds (63%) of all patients had abnormalities detected on brain computerized tomography/magnetic resonance (CT/MR) imaging. After SNP array and WES analysis, the genetic etiology was revealed in 7 out of 24 (29%) cases. Three of the variants detected were novel (SLC12A5, DLG4, SLC9A6). This study revealed for the first time that Smith-Magenis syndrome, SCN8A-related DEE type 13 and SLC12A5 gene variation are involved in the genetic etiology of (D)EE-SWAS. (D)EE-SWAS is a genetically diverse disorder with underlying copy number variations and single-gene abnormalities. In the current investigation, rare novel variations in genes known to be related to (D)EE-SWAS and not previously reported genes to be related to (D)EE-SWAS were discovered, adding to the molecular genetic spectrum. Molecular etiology enables the patient and family to receive thorough and accurate genetic counseling as well as a personalized medicine approach.

Natural history of ENPP1 deficiency: Nationwide Turkish Cohort Study of autosomal-recessive hypophosphataemic rickets type 2.

OBJECTIVE: Autosomal-recessive hypophosphataemic rickets type 2 (ARHR2) is a rare disease that is reported in survivors of generalized arterial calcification of infancy (GACI). DESIGN, PATIENTS AND MEASUREMENT: The objective of this study was to characterize a multicenter paediatric cohort with ARHR2 due to ectonucleotide pyrophosphatase/phosphodiesterase family member 1 (ENPP1) deficiency and with a diagnosis of GACI or GACI-related findings. The clinical, biochemical and genetic characteristics of the patients were retrospectively retrieved. RESULTS: We identified 18 patients from 13 families diagnosed with ARHR2. Fifteen of the patients had an ENPP1 variation confirmed with genetic analyses, and three were siblings of one of these patients, who had clinically diagnosed hypophosphataemic rickets (HRs) with the same presentation. From nine centres, 18 patients, of whom 12 (66.7%) were females, were included in the study. The mean age at diagnosis was 4.2 ± 2.2 (1.6-9) years. The most frequently reported clinical findings on admission were limb deformities (66.6%) and short stature (44.4%). At diagnosis, the mean height SD was -2.2 ± 1.3. Five of the patients were diagnosed with GACI in the neonatal period and treated with bisphosphonates. Other patients were initially diagnosed with ARHR2, but after the detection of a biallelic variant in the ENPP1 gene, it was understood that they previously had clinical findings associated with GACI. Three patients had hearing loss, and two had cervical fusion. After the treatment of HRs, one patient developed calcification, and one developed intimal proliferation. CONCLUSION: ARHR2 represents one manifestation of ENPP1 deficiency that usually manifests later in life than GACI. The history of calcifications or comorbidities that might be associated with GACI will facilitate the diagnosis in patients with ARHR2, and patients receiving calcitriol and phosphate medication should be carefully monitored for signs of calcification or intimal proliferation.

Secondary findings in genes related to cancer phenotypes in Turkish exome sequencing data from 2020 individuals.

Big data generated from exome sequencing (ES) and genome sequencing (GS) analyses can be used to detect actionable and high-penetrance variants that are not directly associated with the primary diagnosis of patients but can guide their clinical follow-up and treatment. Variants that are classified as pathogenic/likely pathogenic and are clinically significant but not directly associated with the primary diagnosis of patients are defined as secondary findings (SF). The aim of this study was to examine the frequency and variant spectrum of cancer-related SF in 2020 Turkish ES data and to discuss the importance of the presence of cancer-related SF in at-risk family members in terms of genetic counseling and follow-up. A total of 2020 patients from 2020 different families were evaluated by ES. SF were detected in 28 unrelated cases (1.38%), and variants in BRCA2 (11 patients) and MLH1 (4 patients) genes were observed most frequently. A total of 21 different variants were identified, with 4 of them (c.9919_9932del and c.3653del in the BRCA2 gene, c.2002A>G in the MSH2 gene, c.26_29del in the TMEM127 gene) being novel variations. In three different families, c.1189C>T (p.Gln397*) variation in BRCA2 gene was detected, suggesting that this may be a common variant in the Turkish population. This study represents the largest cohort conducted in the Turkish population, examining the frequency and variant spectrum of cancer-related SF. With the identification of frequent variations and the detection of novel variations, the findings of this study have contributed to the variant spectrum. Genetic testing conducted in family members is presented as real-life data, showcasing the implications in terms of counseling, monitoring, and treatment through case examples.

The first Turkish family with a novel biallelic missense variant of the ALKBH8 gene: A study on the clinical and variant spectrum of ALKBH8-related intellectual developmental disorders.

ABH8, the protein encoded by the ALKBH8 gene, modifies tRNAs by methylating their anticodon wobble uridine residues. The variations in the ALKBH8 gene are associated with the "intellectual developmental disorder, autosomal recessive type 71" (MIM: 618504) phenotype in the OMIM database. This phenotype is characterized by global developmental delay, facial dysmorphic features, and psychiatric problems. To date, 12 patients from five distinct families carrying variants of the ALKBH8 gene have been reported in the literature. In the present study, we report the first Turkish family harboring a novel homozygous missense variant, NM_138775.3:c.1874G > C (p.Arg625Pro), in the last exon of the ALKBH8 gene. Two affected siblings in this family showed signs of global developmental delay and intellectual disability. Based on the dysmorphological assessment of the cases, fifth finger clinodactyly and fetal fingertip pads were prominent, in addition to the dysmorphic findings similar to those reported in previous studies. Minor dysmorphic limb anomalies in relation to this phenotype have not yet been previously reported in the literature. Our computational studies revealed the potential deleterious effects of the Arg-to-Pro substitution on the structure and stability of the ABH8 methyltransferase domain. In the present report, the first Turkish family with an ultrarare disease associated with the ALKBH8 gene was reported, and a novel deleterious variant in the ALKBH8 gene and additional clinical features that were not reported with this condition have been reported.

Expanding the clinical and immunological phenotypes of PAX1-deficient SCID and CID patients.

Paired box 1 (PAX1) deficiency has been reported in a small number of patients diagnosed with otofaciocervical syndrome type 2 (OFCS2). We described six new patients who demonstrated variable clinical penetrance. Reduced transcriptional activity of pathogenic variants confirmed partial or complete PAX1 deficiency. Thymic aplasia and hypoplasia were associated with impaired T cell immunity. Corrective treatment was required in 4/6 patients. Hematopoietic stem cell transplantation resulted in poor immune reconstitution with absent naïve T cells, contrasting with the superior recovery of T cell immunity after thymus transplantation. Normal ex vivo differentiation of PAX1-deficient CD34+ cells into mature T cells demonstrated the absence of a hematopoietic cell-intrinsic defect. New overlapping features with DiGeorge syndrome included primary hypoparathyroidism (n = 5) and congenital heart defects (n = 2), in line with PAX1 expression during early embryogenesis. Our results highlight new features of PAX1 deficiency, which are relevant to improving early diagnosis and identifying patients requiring corrective treatment.

Chromosomal microarray and exome sequencing in unexplained early infantile epileptic encephalopathies in a highly consanguineous population.

AIM: To identify genetic causes for early infantile epileptic encephalopathies (EIEE) in Turkish children with mostly consanguineous parents. METHODS: In a selected EIEE group (N = 59) based on results of nongenetic and initial genetic testing with unexplained etiology, 49 patients underwent array-based comparative genomic hybridization (aCGH) and 49 patients underwent whole exome sequencing (WES) including 39 with negative aCGH results and 10 with WES-only. RESULTS: Diagnostic yield of aCGH and WES for pathogenic or likely pathogenic variants was 14.3% and 38.8%, respectively. Including de novo variants of uncertain significance linked to compatible phenotypes, increased the diagnostic yield of WES to 61.2%. Out of 38 positive variants, 18 (47.4%) were novel and 16 (42.1%) were de novo. Twenty-one (56.8%) patients had recessive variants inherited from mostly consanguineous healthy parents (85.7%). Fourteen (37.8%) of patients with diagnostic results had positive variants in established EIEE genes. Seizures started during neonatal period in 32.4% patients. Posture or movement disorders were comorbid with EIEE in 40.5% of diagnosed patients. We identified treatable metabolic disorders in 8.1% of patients and pathogenic variants in genes which support using targeted medicine in 19% of patients. CONCLUSIONS: Detailed electro-clinical phenotyping led to expansion of some of the known phenotypes with non-neurological and neurological findings in addition to seizures, as well as suggestion of candidate genes (SEC24B, SLC16A2 and PRICKLE2) and a copy number variant (microduplication of Xp21.1p11.4). The high ratio of recessive inheritance could be important for family counseling.

Identification of novel variants in Turkish families with non-syndromic congenital cataracts using whole-exome sequencing.

PURPOSE: The present study aimed to identify the molecular etiology of non-syndromic congenital cataract (CC) using whole-exome sequencing (WES) analysis. METHODS: In the present study, ophthalmologic results and pedigree analysis of the families of 12 patients with non-syndromic CC were evaluated. WES analysis was conducted after DNA was isolated from peripheral blood samples obtained from the patients. RESULTS: Twelve non-syndromic probands (10 males and 2 females) with bilateral CC were included in the study. Patient age ranged between 1 and 11 months. WES analysis showed pathogenic/likely pathogenic variant in 7 (58%) of the 12 families and variant of unknown significance (VUS) in 5 (42%) of them. All the 13 different variants detected in 9 different CC-related genes were co-segregated with the disease. Autosomal dominant inheritance was found in 7 (58%) of the families and autosomal recessive inheritance was found in 5 (42%) of them. CONCLUSION: To the best of our knowledge, the present research is one of the limited numbers of studies in the Turkish population in which genetically heterogeneous non-syndromic CC was investigated using WES analysis. Novel variants that we identified in DNMBP, LSS, and WFS1 genes, which are rarely associated with the CC phenotype, have contributed to the mutation spectrum of this disease. Identifying the relevant molecular genetic etiology allows accurate genetic counseling to be provided to the families.

Evaluation of optical coherence tomography findings and visual evoked potentials in Charcot-Marie-Tooth disease.

PURPOSE: To evaluate the spectral-domain optical coherence tomography (SD-OCT) findings and pattern visual evoked potential (VEP) in Charcot-Marie-Tooth (CMT) disease. METHODS: Seventeen patients with CMT disease and 17 control subjects were included in the study. The patients were divided into two groups according to conduction velocity and inheritance pattern as demyelinating type (CMT 1) and axonal type (CMT 2). The average retinal nerve fiber layer (RNFL) thickness, RNFL thicknesses of all quadrants, and thicknesses of the ganglion cell layer complex (GCC) were measured using SD-OCT. Pattern VEP recordings were evaluated in both groups. RESULTS: The average and four quadrants of RNFL thicknesses, and superior and inferior GCC thicknesses were significantly thinner in the CMT patients compared with healthy individuals, but there were no statistically significant differences between the CMT groups. There was a significant positive correlation between age and all RNFL and GCC thicknesses in the CMT 2 group and between age and RNFL thickness of the temporal quadrant in the CMT 1 group. P100 latencies were significantly delayed in the CMT groups compared with controls, and there were no significant differences in P100 latencies between the CMT groups (p < 0.001). VEP amplitudes were in normal ranges in the CMT groups. CONCLUSION: This study showed that RNFL and GCC thicknesses were significantly reduced and VEP latencies were prolonged in patients with CMT with normal clinical examinations. Our results suggest that optic nerves may be affected more frequently in patients with CMT that is detected in clinical examinations.

Microstructural evaluation of the brain with advanced magnetic resonance imaging techniques in cases of electrical status epilepticus during sleep (ESES).

Background/aim: The cause and treatment of electrical status epilepticus during sleep (ESES), one of the epileptic encephalopathies of childhood, is unclear. The aim of this study was to evaluate possible microstructural abnormalities in the brain using advanced magnetic resonance imaging (MRI) techniques in ESES patients with and without genetic mutations. Materials and methods: This research comprised 12 ESES patients without structural thalamic lesions (6 with genetic abnormalities and 6 without) and 12 healthy children. Whole-exome sequencing was used for the genetic mutation analysis. Brain MRI data were evaluated using tractus-based spatial statistics, voxel-based morphometry, a local gyrification index, subcortical shape analysis, FreeSurfer volume, and cortical thickness. The data of the groups were compared. Results: The mean age in the control group was 9.05 ± 1.85 years, whereas that in the ESES group was 9.45 ± 2.72 years. Compared to the control group, the ESES patients showed higher mean thalamus diffusivity (p < 0.05). ESES patients with genetic mutations had lower axial diffusivity in the superior longitudinal fasciculus and gray matter volume in the entorhinal region, accumbens area, caudate, putamen, cerebral white matter, and outer cerebellar areas. The superior and middle temporal cortical thickness increased in the ESES patients. Conclusion: This study is important in terms of presenting the microstructural evaluation of the brain in ESES patients with advanced MRI analysis methods as well as comparing patients with and without genetic mutations. These findings may be associated with corticostriatal transmission, ictogenesis, epileptogenesis, neuropsychiatric symptoms, cognitive impairment, and cerebellar involvement in ESES. Expanded case-group studies may help to understand the physiology of the corticothalamic circuitry in its etiopathogenesis and develop secondary therapeutic targets for ESES.

Molecular characterization of Turkish patients with demyelinating Charcot-Marie-Tooth disease.

Charcot-Marie-Tooth (CMT) disease represents a distinct subgroup of inherited peripheral neuropathies with a significant prevalence throughout the world and manifests both phenotypic and genetic heterogeneity. Electrophysiological studies subclassify CMT mainly as demyelinating or axonal types. In this study, we investigated the molecular characteristics of a Turkish cohort of 23 probands out of 34 symptomatic demyelinating CMT individuals from January 2019 to December 2021. In order to identify the underlying genetic cause, we applied a rational algorithm: PMP22 gene was initially analyzed for duplication, if PMP22-duplication testing was negative, other most causative genes (GJB1, MPZ) and PMP22 were then sequenced and if no variant was detected at aforementioned tests, whole exome sequencing (WES) test was finally performed. A total of 17 patients (≅ 74%; n = 23) were found to harbor a disease-causing variant in demyelinating CMT-related genes and among the variants, PMP22-duplication was the most frequent (≅ 41%). CMT1, CMTX, and CMT4 subtypes were manifested in ten, five, and two individuals respectively. GJB1 and SBF2 genes were the only detected genes associated with the CMTs other than CMT1. We also reported totally five novel variants: c.379A > C (p.Ile127Leu) and c.548G > T (p.Arg183Leu) variants in GJB1, c.988G > T (p.Glu330Ter) variant in NEFL, c.765_770delCCCTAT (p.Pro256_Ile257del) and c.2552A > C (p.His851Pro) variants in SBF2. As the understanding of pathophysiology and molecular mechanisms of CMT continues to evolve rapidly, many therapeutic strategy options including promising small-molecular compounds, gene replacement therapy, or disease-modifying therapies will soon be implemented in the clinical setting.

Novel LNPK variant causes progressive cerebral atrophy: Expanding the clinical phenotype.

The biallelic variations of the LNPK gene are associated with the "neurodevelopmental disorder with epilepsy and hypoplasia of the corpus callosum" phenotype [MIM:618090] in the Online Mendelian Inheritance In Men database, and so far, two families have been identified in the literature. A third family with novel clinical features, who bears a novel variant in LNPK (NM_030650.3: c.770delA, p.D257fs*31) is described in the present study. The coexistence of psychomotor regression and neurodegeneration in brain magnetic resonance imaging was found for the first time in the present study, thanks to the long-term follow-up data on the case, which contributed to the phenotypic and mutation spectrum by means of the novel variation.

Familial Hypomagnesemia with Hypercalciuria and Nephrocalcinosis Due to CLDN16 Gene Mutations: Novel Findings in Two Cases with Diverse Clinical Features.

Biallelic loss of function mutations in the CLDN16 gene cause familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC), and chronic kidney disease. Here we report two cases of FHHNC with diverse clinical presentations and hypercalcemia in one as a novel finding. Pt#1 initially presented with urinary tract infection and failure to thrive at 5.5 months of age to another center. Bilateral nephrocalcinosis, hypercalcemia (Ca: 12.2 mg/dl), elevated parathyroid hormone (PTH) level, and hypercalciuria were detected. Persistently elevated PTH with high/normal Ca levels led to subtotal-parathyroidectomy at the age of 2.5. However, PTH levels remained elevated with progressive deterioration in renal function. At 9-year-old, she was referred to us for evaluation of hyperparathyroidism and, hypomagnesemia together with hypercalciuria, elevated PTH with normal Ca levels, and medullary nephrocalcinosis were detected. Compound heterozygosity of CLDN16 variants (c.715G>A, p.G239R; and novel c.360C>A, p.C120*) confirmed the diagnosis. Pt#2 was a 10-month-old boy, admitted with irritability and urinary crystals. Hypocalcemia, hypophosphatemia, elevated PTH and ALP, low 25(OH)D levels, and radiographic findings of rickets were detected. However, additional findings of hypercalciuria and bilateral nephrocalcinosis were inconsistent with the nutritional rickets. Low/normal serum Mg levels suggested the diagnosis of FHHNC which was confirmed genetically as a homozygous missense (c.602G > A; p.G201E) variant in CLDN16. Yet, hypocalcemia and hypomagnesemia persisted in spite of treatment. In conclusion, FHHNC may present with diverse clinical features with mild hypomagnesemia leading to secondary hyperparathyroidism with changing Ca levels from low to high. Early and accurate clinical and molecular genetic diagnosis is important for proper management.

Whole-exome sequencing reveals new potential genes and variants in patients with premature ovarian insufficiency.

PURPOSE: Premature ovarian insufficiency (POI) is a heterogeneous disorder characterized by the cessation of menstrual cycles before the age of 40 years due to the depletion or dysfunction of the ovarian follicles. POI is a highly heterogeneous disease in terms of etiology. The aim of this study is to reveal the genetic etiology in POI patients. METHODS: A total of 35 patients (mean age: 27.2 years) from 28 different families diagnosed with POI were included in the study. Karyotype, FMR1 premutation analysis, single nucleotide polymorphism (SNP) array, and whole-exome sequencing (WES) were conducted to determine the genetic etiology of patients. RESULTS: A total of 35 patients with POI were first evaluated by karyotype analysis, and chromosomal anomaly was detected in three (8.5%) and FMR1 premutation was detected in six patients (17%) from two different families. A total of 29 patients without FMR1 premutation were included in the SNP array analysis, and one patient had a 337-kb deletion in the chromosome 6q26 region including PARK2 gene, which was thought to be associated with POI. Twenty-nine cases included in SNP array analysis were evaluated simultaneously with WES analysis, and genetic variant was detected in 55.1% (16/29). CONCLUSION: In the present study, rare novel variants were identified in genes known to be associated with POI, which contribute to the mutation spectrum. The effects of detected novel genes and variations on different pathways such as gonadal development, meiosis and DNA repair, or metabolism need to be investigated by experimental studies. Molecular etiology allows accurate genetic counseling to the patient and family as well as fertility planning.

Secondary findings in 622 Turkish clinical exome sequencing data.

CES (Clinical Exome Sequencing) is a method that we use to diagnose rare diseases with nonspesific clinical features. Besides primary indication for testing genetic information may be detected about diseases which have not yet emerged. ACMG guidelines recommend to report pathogenic variations in medically actionable 59 genes. In this study we evaluated CES data of 622 cases which were tested for various indications. According to ACMG recommendations 59 genes were screened for reportable variations. The detected variations were reviewed using distinct databases and ACMG variation classification guidelines. Among 622 cases 13 (2.1%) had reportable variations including oncogenetic, cardiogenetic disorders, and malignant hyperthermia susceptibility-related genes. In 15 cases (2.4%) heterozygous pathogenic and likely pathogenic variations were detected in genes showing autosomal recessive inheritance. Ten novel variations causing truncated protein or splicing defect were reported. We detected 11 variations having conflicting interpretations in databases and 30 novel variations, predicted as likely pathogenic via insilico analysis tools which further evaluations are needed. As to our knowledge this is the first study investigating secondary findings in Turkish population. To extract the information that may lead to prevent severe morbidities and mortalities from big data is a valuable and lifesaving effort. Results of this study will contrbute to existing knowledge about secondary findings in exome sequencing and will be a pioneer for studies in Turkish population.

Somatic STK11 mosaicism in a Turkish patient with Peutz-Jeghers syndrome.

Peutz-Jeghers syndrome (PJS) is an autosomal dominant disorder, caused by germline variants in the serine/threonine kinase 11 (STK11) gene. However, mosaic variants in STK11 gene have been rarely described. A 25-year-old woman diagnosed with PJS due to multiple hamartomatous polyps in the gastrointestinal tract was referred to our clinic. In the molecular diagnosis, the patient was evaluated using the STK11 gene sequence analysis and multiplex ligation-dependent probe amplification (MLPA) method, which suggested no pathogenic variant to account for the clinical picture. Given that the clinical findings of the patient were consistent with those of PJS, the raw data from next-generation sequencing (NGS) were re-examined for mosaicism which led to the detection of a novel mosaic c.920 + 1G > T variant in STK11 gene with a rate of 23% (1860x). Deep read-level NGS was performed on buccal mucosa and polyp samples to determine mosaicism levels in other tissues. Variant frequencies were 29% (710x) and 31% (1301x), respectively. Mosaicism should be considered in cases with clear clinical diagnostic criteria, such as PJS, where the pathogenic variant cannot be detected by sequence analysis and MLPA methods. Identification of mosaicism in these patients is very important as it can have an impact on patient follow-up and genetic counseling for relatives.

Prediction of molecular phenotypes for novel SCN1A variants from a Turkish genetic epilepsy syndromes cohort and report of two new patients with recessive Dravet syndrome.

Dravet syndrome and genetic epilepsy with febrile seizures plus (GEFS+) are both epilepsy syndromes that can be attributed to deleterious mutations occurring in SCN1A, the gene encoding the pore-forming α-subunit of the NaV 1.1 voltage-gated sodium channel predominantly expressed in the central nervous system. In this research endeavor, our goal is to expand our prior cohort of Turkish patients affected by SCN1A-positive genetic epilepsy disorders. This will be accomplished by incorporating two recently discovered and infrequent index cases who possess a novel biallelic (homozygous) SCN1A missense variant, namely E158G, associated with Dravet syndrome. Furthermore, our intention is to use computational techniques to predict the molecular phenotypes of each distinct SCN1A variant that has been detected to date within our center. The correlation between genotype and phenotype in Dravet syndrome/GEFS+ is intricate and necessitates meticulous clinical investigation as well as advanced scientific exploration. Broadened mechanistic and structural insights into NaV 1.1 dysfunction offer significant promise in facilitating the development of targeted and effective therapies, which will ultimately enhance clinical outcomes in the treatment of epilepsy.

Severe Early-Onset Obesity and Diabetic Ketoacidosis due to a Novel Homozygous c.169C>T p.Arg57* Variant in CEP19 Gene.

Introduction: Early-onset severe obesity is usually the result of an underlying genetic disorder, and several genes have recently been shown to cause syndromic and nonsyndromic forms of obesity. The "centrosomal protein 19 (CEP19)" gene encodes for a centrosomal and ciliary protein. Homozygous variants in the CEP19 gene are extremely rare causes of early-onset severe monogenic obesity. Herein, we present a Turkish family with early-onset severe obesity with variable features. Methods: Sanger sequencing and whole-exome sequencing were performed to identify the genetic etiology in the family. Results: The index case was a 12-year-old female who presented with severe obesity (BMI of 62.7 kg/m2), metabolic syndrome, and diabetic ketoacidosis. Her nonidentical twin female siblings also had early-onset severe obesity, metabolic syndrome, and diabetes. In addition, one of the affected siblings had situs inversus abdominalis, polysplenia, lumbar vertebral fusion, and abnormal lateralization. A novel homozygous nonsense (c.169C>T, p. Arg57*) pathogenic variant was detected in exon 3 of the CEP19 gene in all affected members of the family. One unaffected sister and unaffected parents were heterozygous for the variant. This variant is predicted to cause a stop codon at amino acid sequence 57, leading to a truncated CEP19 protein. Discussion/Conclusion: Our study expands the phenotypical manifestations and variation database of CEP19 variants. The findings in one of our patients reaffirm its role in the assembly and function of both motile and immotile cilia.

A Rare Presentation of Homozygous Pathogenic Variant in MC2R Gene with Salt-Wasting Crisis in a Neonate.

Introduction: Familial glucocorticoid deficiency (FGD) is a rare autosomal recessive disease resulting from isolated glucocorticoid deficiency or unresponsiveness to adrenocorticotropic hormone. Patients with FGD usually present in infancy or early childhood with hyperpigmentation, recurrent infections, and hypoglycemia. The salt-wasting crisis is rare. Case Presentation: A term female neonate was admitted to the neonatal intensive care unit due to respiratory distress. On physical examination, she had generalized hyperpigmentation. Initial laboratory work-up yielded normal serum electrolytes and glucose. Hyponatremia and hyperkalemia emerged on follow-up. The patient was diagnosed as having primary adrenal insufficiency (PAI) with elevated plasma adrenocorticotropin hormone and reduced cortisol levels and hydrocortisone. We started on oral sodium (5 mEq/kg/day) and fludrocortisone (FC) (0.2 mg/day) treatment to the patient. Ultrasonography revealed hypoplastic adrenal glands. Molecular genetic analysis revealed a previously reported homozygous pathogenic variant NM_000529.2: c.560delT (p.V187fs*29) in the MC2R gene. FC dose was tapered to 0.05 mg/day on the third month of life and was stopped at tenth months of age with maintenance of normal serum electrolytes and clinical findings. Conclusion: FGD due to MC2R gene mutation may rarely present with a salt-wasting crisis in the neonatal period. Identifying the causative gene with the pathogenic variant in PAI may serve to individualize a treatment plan.

De novo Pure Partial Trisomy 6p Associated with Facial Dysmorphism, Developmental Delay, Brain Anomalies, and Primary Congenital Hypothyroidism.

Introduction: Partial trisomy 6p is a rare chromosomal anomaly, characterized by low birth weight, developmental delay, craniofacial abnormalities, feeding difficulties, congenital heart defects, and renal abnormalities. Some of the partial trisomy 6p cases reported in the literature included partial monosomy of another chromosome. This is often due to the fact that one of the parents is a balanced translocation carrier, thereby making it difficult to determine the genotype-phenotype relationship. Pure partial trisomy 6p cases are even rarer and may occur as a result of a marker chromosome, tandem or inverted duplication, and interchromosomal insertion. Case Presentation: In this study, we evaluated the physical characteristics and genetic data of a 2-year-old girl with developmental delay and facial dysmorphic features. Dysmorphology assessment revealed the presence of a prominent forehead, short and narrow palpebral fissures, blepharoptosis, convex nasal ridge, hemangioma on the left eyelid, high-arched palate, retromicrognathia, and low-set ears. The patient‧s G-banded karyotype was 46,XX,der(2)t(2;6)(q37.3;p22.1). Upon SNP-array analysis, aimed to determine the origin of the extra chromosomal material detected in chromosome 2 of the patient, there was a de novo 27.5-Mb duplication at 6p, arr[GRCh37] 6p25.3p22.1(204,909_27,835,272)×3, interpreted to be pathogenic. Conclusion: We present this case report to clarify the clinical findings of a rare chromosomal anomaly, discuss the genes that may be related to the phenotype and contribute to the literature in terms of knowledge regarding genotype-phenotype correlation.