Homozygous Gene Mutation Research Articles

Case Report and Literature Review: Homozygous DNAJC3 Mutation in a Saudi Family Causing Maturity Onset Diabetes of the Young (MODY), Hypothyroidism, Short Stature, Neurodegeneration, and Hearing Loss

Introduction: Monogenic diabetes results from a mutation in single gene, predominantly inherited and typically affects the young. DNAJC3 acts in attenuating endoplasmic reticulum stress and is found in abundance in pancreatic tissue. Clinical Case: We report a homozygous DNAJC3 mutation in two siblings of a consanguineous Saudi family. A 3-year boy presented with short stature and thyroid nodule; lab findings confirmed hypothyroidism, with TSH 27.8 and FT4 6.7 (n: TSH:0.35-4.94 mIU/L, FT4:9.0-19 pmol/L). Subsequently, L-thyroxine was started. GH stimulation test was normal. He was severely short; 80.5 cm (< 1 percentile, -3.79 SD). The patient developed sensorineural hearing loss (SNHL) at 6 years. He had low intellectual function and weak school performance. GH treatment was postponed to age 9 due to strong family history of DM. At that point, the patient developed progressive ataxic gait, for which he had muscle biopsy that excluded mitochondrial disease and workup for multiple sclerosis, which was excluded. Brain and spine MRI showed prominent neurodegeneration in subcortical white matter. At age 11, the patient developed DM, 4 years after GH treatment initiation. DM autoimmune markers were negative on multiple occasions. Lifestyle modification was initiated but soon required basal and bolus insulin therapy. Whole exome sequencing revealed homozygous DNAJC3 mutation, which explained his clinical presentation. At age of 17, adult height was 141 cm (Z-score: -5.87). His older brother had similar history discovered retrospectively but did not develop neurodegeneration or ataxia from the same DNAJC3 mutation. Literature Review: Literature review revealed six individuals with homozygous DNAJC3 mutation. All patients developed DM, with onset ranging from 11 to 19 years, highly suggestive of MODY. Other endocrine manifestations included short stature, and hypothyroidism due to primary etiology; in view of elevated TSH levels, vs. being secondary, as suggested by the authors. All patients had mitochondrial disease workups and was excluded. Variable neurodegeneration degrees are described; SNHL, progressive ataxia, sensorimotor neuropathy, and cognitive deficits. MRI findings showed atrophy of cerebellum, brainstem, cervical spinal cord, and hyperintense T2 lesions typical of neurodegeneration. Conclusion: Homozygous DNAJC3 gene mutation fits MODY criteria, we propose recognizing it as one of the known MODY gene mutations. Hypothyroidism is due to primary etiology, evident by TSH spikes. Physicians evaluating mitochondrial disease in patients with a constellation of SNHL, DM, hypothyroidism, neurodegeneration, and short stature should suspect DNAJC3 as one differential diagnosis. GH treatment must be initiated cautiously, with close monitoring due to its known diabetogenic effect, especially in DNAJC3 mutations, defective endoplasmic stress attenuation mechanism.

Generation and characterization of three human induced pluripotent stem cell lines (iPSC) from two family members with dilated cardiomyopathy and left ventricular noncompaction (DCM-LVNC) and one healthy heterozygote sibling

Autophagy serves as a master regulator of cellular homeostasis. Hence, expectedly autophagic dysfunction has been documented in many diseases such as cancer, neurodegeneration and cardiovascular disorders. A novel homozygous mutation in PLEKHM2 gene (mPLEKHM2) resulted in dilated cardiomyopathy with left ventricular noncompaction (DCM-LVNC), probably as result of impaired autophagy due to disruption of lysosomal movement assisted by PLEKHM2. Here we report a generation of three iPSC lines, four clones originated from two patients with homozygous mPLEKHM2 and two from a heterozygote sibling. All generated lines highly expressed pluripotency markers, spontaneously differentiated into three germ layers, retained the mutation after reprogramming and displayed normal karyotypes.

Persistent Hyperinsulinemic Hypoglycemia in Infancy-A Case Report

&#x0D; &#x0D; &#x0D; &#x0D; Persistent hyperinsulinemic hypoglycemia of infancy (PHHI) is one of the commonest reasons for severe, intractable hypoglycemia in neonates. Dysregulated insulin secretion is the major underlying pathogenesis which results in hyperinsulinemia, hypoketonemia and hypofatty acidemia. The management is extremely complicated. Early diagnosis and aggressive management of hyperinsulinemic hypoglycemia is essential for prevention of hypoglycemia induced neuronal injury. Here we describe a baby diagnosed as PHHI who was unresponsive to medical management with diazoxide and underwent near total pancreatectomy. Genetic work up revealed a homozygous termination mutation in ABCC8 gene at amino acid position 1452 with heterozygosity in both parents.&#x0D; &#x0D; &#x0D; &#x0D;

POS-418 HOMOZYGOUS MUTATION IN COMPLEMENT C3 GENE ASSOCIATED WITH FAMILIAL HEMOLYTIC UREMIC SYNDROME: CASE SERIES

Atypical hemolytic syndrome (aHUS) is a rare renal disease. It has been recognized to be due to genetic mutations in more than 60 % of cases. Its pathogenesis has been characterized to be secondary to Alternative complement pathway dysregulation. We aim to report the genotypic and phenotypic features of homozygous mutation in C3 gene in three infants in three different families from the same tripe. We will go through their early sever presentations, courses, responses to treatment with anti-C5 monoclonal antibody, and their current conditions.

EP124 - Neonatal severe hyperparathyroidism caused by homozygous mutation in CASR gene: A rare cause of life-threatening hypercalcemia

eP124 - Neonatal severe hyperparathyroidism caused by homozygous mutation in CASR gene: A rare cause of life-threatening hypercalcemia

EP251 - Homozygous LNPK gene mutation in neurodevelopmental disorder: case report

eP251 - Homozygous LNPK gene mutation in neurodevelopmental disorder: case report

Reduced fibroblast growth factor 21 and β-Klotho secretion in untreated congenital isolated GH deficiency.

Increasing evidence suggests that the FGF-Klotho endocrine system and the somatotropic system (pituitary and extra-pituitary GH) may have important metabolic and immune relationships, thus contributing to the pathophysiology of aging-related disorders, including diabetes, atherosclerosis, and cancer. The status of these interactions in isolated GH deficiency (IGHD) is unknown. The objective of this study was to assess the response of both FGF21 and β-Klotho levels to a standard meal in a homogeneous group of adults with congenital untreated IGHD due to a homozygous mutation in the GHRH receptor gene. In a cross-sectional study, we measured the levels of FGF21 and β-Klotho, before and 30, 60, 120, and 180 min after a standardized test meal in 20 (11 males) IGHD and 20 (11 males) age-matched controls. Areas under the curves (AUC) of FGF21 and β-Klotho were calculated. Baseline levels of FGF21 were similar, but baseline levels of β-Klotho were lower in IGHD subjects. The IGHD individuals exhibited lower AUC for FGF21 and β-Klotho levels than control subjects. There was a positive correlation between IGF1 and β-Klotho levels in the pooled groups. No correlation was found between IGF1 and FGF21 levels. Subjects with lifetime, untreated IGHD exhibit reduced FGF21 and β-Klotho levels response to a mixed meal. This difference may have consequences on metabolism and aging.

Homozygous Mutation in the Insulin Receptor Gene Associated with Mild Type A Insulin Resistance Syndrome: A Case Report

Insulin receptor (INSR) mutations lead to heterogeneous disorders that may be as severe as Donohue syndrome or as mild as “type A insulin resistance syndrome”. Patients with severe disorders usually harbor homozygous or compound heterozygous mutations. In contrast, type A insulin resistance syndrome has been associated with heterozygous mutations; homozygous mutations are rarely responsible for this condition. We report a novel, homozygous mutation, p.Leu260Arg in exon 3, of the INSR gene in a female adolescent patient with type A insulin resistance syndrome together with clinical details of her medical follow-up. Different mutations in the INSR gene cause different phenotype and vary depending on the inheritance pattern. This report adds to the literature, increases understanding of the disease mechanism and aids in genetic counseling.

Hypo-cortisolism, early onset obesity and liver disease in a child with homozygous proopiomelanocortin mutation

The peptide derivatives of proopiomelanocortin molecule are involved in energy homeostasis, regulation of food intake, skin pigmentation and augment biliary flow. Homozygous mutation in POMC gene, which is inherited in an autosomal recessive pattern, is associated with hyperphagia leading to early onset obesity, hypoglycaemia and neonatal cholestasis due to cortisol deficiency and red hair pigmentation as a result of alpha MSH deficiency. We report a child having multiple episodes of hypoglycemia with this disorder who presented like liver disease. Our case report highlights the importance of early suspicion of this rare condition and confirmation with genetic analysis.

Early onset familial relapsing polyneuropathy, mimicking CIDP; A lesson from clinical genetics

Background: In children, chronic immune-mediated neuropathies present with slowly progressive or relapsing episodes of gait difficulty, symmetric weakness and sometimes paraesthesia. Infancy and early childhood age of presentation and familial recurrence are believed to be atypical features.&#x0D; Case presentation: Herein, we describe two brothers from a non- consanguineous Iraqi family, who presented with episodes of acute immune-mediated demyelinating peripheral neuropathy in early infancy that relapsed recurrently. Mild haemolytic anaemia was also reported. Inherited metabolic disorders were suspected and Whole Exome Sequencing of the youngest brother revealed homozygous frame shift mutation in CD59 gene, confirming the diagnosis of autosomal recessive hemolytic anemia, CD59-mediated, with or without immune-mediated polyneuropathy (HACD59).&#x0D; Conclusion: The report highlights the advantage of genetic testing in such rare and inherited conditions. In the lack of necessary non-traditional diagnostic methods, it is substantial to maintain the accustomed medical practice and strategies, based on available clinical data.

493 Using human monogenic disease to quantify the contribution of fetal insulin to birth weight

Fetal insulin affects birth weight, but the extent of this relationship has not been established in humans, nor whether it has any implications for postnatal growth. We sought to investigate this by studying birth size and postnatal growth in individuals with monogenic diseases which result in absent insulin secretion in utero. We studied birth size in individuals with a homozygous insulin gene (INS) mutation or pancreatic agenesis (n=64 for weight, n=17 for length) born after 31 weeks gestation and compared with international growth standards for gestational age and sex (SDS). Postnatal growth was studied in individuals with INS mutations. We analyzed serial measures of weight and length until the age of four years (n=10 and 9, respectively) and most recent available weight and height (n=16 and 15, respectively). In all individuals birth weight and length were low (median (IQR) SDS -3.11 (-3.53,-2.61) and -2.86 (-3.62,-1.90), respectively). Birth weight adjusted to 40 weeks gestation was 1711 g (95% CI 1601,1821 g) vs expected of 3320 g (Fig. 1), showing non-insulin-mediated growth represents 52% of normal birth weight at term. Catch-up growth was rapid with median (IQR) weight and length SDS -0.27 (-0.37,-0.17) and -0.30 (-1.33,0.002), respectively, at 12 months, and 0.02 (-0.35,0.78) and 0.00 (-0.34,0.21), respectively, at 24 months (Fig. 2). Most recent available weight and height SDS were 0.19 (-0.67,1.33) and -0.78 (-1.78,-0.19), respectively. Monogenic diseases resulting in absent fetal insulin have enabled us to answer fundamental questions about early growth in humans. Ultimately, fetal insulin accounts for half of birth weight at term and could be an important cause of fetal growth restriction that is characterised by rapid catch-up growth. Future studies investigating outcomes arising from low and high birth weight should determine differences in insulin and non-insulin-mediated fetal growth, and consider whether they might have different implications for pregnancy outcomes and long-term risk of disease.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Adult glut3 homozygous null mice survive to demonstrate neural excitability and altered neurobehavioral responses reminiscent of neurodevelopmental disorders

Since GLUT3 is vital for fueling neurotransmission, we examined in-vivo the adult phenotype carrying the conditional homozygous glut3 gene mutation (KO) in glutamate-excitatory neurons. These KO mice demonstrated sex-specific differences in brain and body weights (p = 0.0001 and p = 0.01 each) with reduced GLUT3 protein in cerebral cortices and brain stem (p = 0.005). In patch clamp studies the glut3 KO mice displayed a shorter latency to and enhanced paroxysmal activity (p = 0.01 and p = 0.015 each) in pyramidal neurons upon application of a GABAA antagonist, supporting hyperexcitability. Further, associated changes in neurobehavior consisted of reduced latency to fall in the rotorod motor test related to incoordination, increased distance traveled in total and periphery versus center in open field testing suggesting hyperactivity with anxiety (p = 0.0013 in male, p = 0.045 in female), reduced time freezing reminiscent of disrupted contextual fear conditioning (p = 0.0033), decreased time in target quadrant seen with spatial cognitive memory water maze testing (p = 0.034), and enhanced sociability particularly for novelty reflecting a lack of inhibition/impulsivity (p = 0.038). Some of these features were equally pronounced in males and females (cognitive) while others were seen in females (anxiety and impulsivity). We conclude that GLUT3 in adult glutamate-excitatory neurons is essential for maintaining neurotransmitory equipoise regulating excitation with maintenance of motor coordination and activity, cognition, spatial memory and normal fear for both contextual events and novelty with tempered sociability. While sex-specificity was forthcoming for some of these behaviors, our findings collectively suggest that loss-of-function glut3 gene mutations or polymorphisms may underlie an endophenotype of attention deficit-hyperactivity disorder.

An induced pluripotent stem cell line (SDQLCHi033-A) derived from a patient with maple syrup urine disease type Ib carrying a homozygous mutation in BCKDHB gene.

Maple syrup urine disease (MSUD) type Ib is a subclass of MSUD (248600) which is an inborn error of metabolism caused by defects in the branched-chain α-ketoacid dehydrogenase complex. An induced pluripotent stem cell (iPSC) line was generated from an 11-day-old girl diagnosed with maple syrup urine disease type Ib and carrying a novel homozygous mutation of c.1097C>A (p.P366Q) in BCKDHB gene. This cell line demonstrates a normal karyotype and maintains a pluripotent state, displaying the capability to differentiate into the three germ layer lineages and the absence of exogenous pluripotency vector expression.

Rare association of septic arthritis with neonatal diabetes in a patient with PDX-1 mutation

We present a 58-day-old male infant with neonatal diabetes and septic arthritis of hip. He was born of a consanguineous marriage at 35 weeks of gestation and was asymptomatic till presentation. Family history revealed his older sibling had suffered from meningitis and a second sibling had neonatal diabetes (died due to an unknown infection). Our patient underwent arthroscopy for septic arthritis and symptoms resolved after antibiotic therapy. Genetic testing was performed for the lipopolysaccharide-responsive beige-like anchor (LRBA) mutation (known to be associated with neonatal diabetes and autoimmune disorders); however, the result revealed a homozygous mutation in PDX-1 gene which is known to cause neonatal diabetes with or without exocrine pancreatic insufficiency. Our case suggests that in neonatal diabetes with atypical infections, genetic causes other than LRBA mutation, like PDX-1 mutation, may be suspected. A genetic diagnosis aids both in treatment and prognostication of neonatal diabetes.

Early Onset of Combined Oxidative Phosphorylation Deficiency in Two Chinese Brothers Caused by a Homozygous (Leu275Phe) Mutation in the C1QBP Gene.

Mitochondrial diseases constitute a group of heterogeneous hereditary diseases caused by impairments in mitochondrial oxidative phosphorylation and abnormal cellular energy metabolism. C1QBP plays an important role in mitochondrial homeostasis. In this study, clinical, laboratory examinations, 12-lead electrocardiographic, ultrasonic cardiogram, and magnetic resonance imaging data were collected from four members of a Chinese family. Whole exome were amplified and sequenced for the proband. The structure of protein encoded by the mutation was predicted using multiple software programs. The proband was a 14-year old boy with myocardial hypertrophy, exercise intolerance, ptosis, and increased lactate. His 9-year old brother exhibited similar clinical manifestations while the phenomenon of ptosis was not as noticeable as the proband. The onset of this disease was in infancy in both cases. They were born after uneventful pregnancies of five generation blood relative Chinese parents. A homozygous mutation (Leu275Phe) in the C1QBP gene was identified in both brothers in an autosomal recessive inherited pattern. Their parents were heterozygous mutation carriers without clinical manifestations. We demonstrated that a homozygous C1QBP- P.Leu275Phe mutation in an autosomal recessive inherited mode of inheritance caused early onset combined oxidative phosphorylation deficiency 33 (COXPD 33) (OMIM:617713) in two brothers from a Chinese family.

Roberts sendromu olgusu: Ultrasonografik özellikleri ve genetik tanısı

Objective: Roberts syndrome is a very rare genetic disease, and it has an autosomal recessive inheritance pattern. It develops as a result of the mutation in ESCO2 gene located in the 8th chromosome. In our study, we aimed to present a case which was found to have Roberts syndrome coexisting with multiple anomalies, particularly skeletal system anomaly, in the 17 weeks of gestation. Case(s): In the fetal ultrasonographic evaluation performed on the pregnant women who referred to our hospital for routine gestational examination in the 17 weeks of gestation, anomalies in the bilateral upper and lower extremities, contracted legs, bilateral cleft palate and lip, intrauterine growth restriction and cardiac anomaly were found in the fetus. Roberts syndrome was considered first with these ultrasonographic findings. The diagnosis of Roberts syndrome was confirmed by cytogenetic and molecular analyses. Early segregation of centromeres and early breaking up of heterochromatic regions near centromeres were found at metaphase stage. By cytogenetic and molecular analyses, homozygous mutation in ESCO2 gene of the fetus and heterozygous mutation in the parents were found. The termination of pregnancy was decided after the genetic consultation with the parents. Physical examination findings and prenatal ultrasound findings after termination were found similar. Conclusion: Many severe skeletal dysplasia cases can be diagnosed ultrasonographically before 20 weeks of gestation. Early diagnosis ensures to take necessary actions for medical support during postnatal period and in terms of labor if pregnancy continues as well as genetic consultation opportunity. If the genetic disease that causes skeletal dysplasia can be identified and parents are found to have this gene, healthy pregnancies can be achieved by obtaining normal embryos via pre-implantation genetic diagnosis in order to prevent the relapse of the disease.

A novel case of homozygous LDLRAP1 gene mutation causing autosomal recessive familial hypercholesterolemia in Kuwait

Background and Aims: Homozygous Familial Hypercholesterolemia (HoFH) is a rare genetic, autosomal disease characterized by high serum low density lipoprotein cholesterol (LDL-C), associated with characteristic clinical manifestations such as tendinous xanthomas and corneal arcus. Although the HoFH and the autosomal recessive familial hypercholesterolemia (ARH) share biochemical and phenotypical characteristics, the clinical diagnosis and management of ARH is challenging and requires confirmatory molecular diagnosis. Case description: a 15-year-old Kuwaiti boy presented to the polyclinic with symptoms of polyuria and polydipsia. Initial blood work up showed Total Cholesterol of 15 mmol/L with normal blood glucose. He was referred to the lipid outpatient clinic with clinical signs of hypercholesterolemia (eruptive xanthomas, bilateral tendon xanthomas, and corneal arcus) and abnormal lipid parameters (LDL-C 8.73 mmol/L, TC 10.55 mmol/L.) He was diagnosed with Familial Hypercholesterolemia (FH) based on the Dutch Lipid Clinic diagnostic criteria.

Hereditary spastic paraplegia with thin corpus callosum due to novel homozygous mutation in SPG11 gene

The most common form of autosomal recessive hereditary spastic paraplegia (HSP) is caused by mutations in SPG11/KIAA1840 gene, which encodes for spatacsin. The clinical presentation of SPG11 is characterized by cognitive impairment, peripheral neuropathy and a thin corpus callosum in brain magnetic resonance imaging. We identified a novel homozygous nonsense mutation (c.6082C>T [p.Q2028]) in exon 32 of SPG11 in Korean siblings. Our findings suggest that this novel homozygous mutation in SPG11 is associated with HSP and with dysgenesis of the corpus callosum. Key Words: Corpus callosum · Hereditary spastic paraplegia · SPG11 · Spatacsi.

A homozygous stop gain mutation in BOD1 gene in a Lebanese patient with syndromic intellectual disability.

Intellectual disability (ID) is a neurodevelopmental disorder characterized by limitations in both intellectual and behavioral functioning. It can occur in non-syndromic and syndromic forms involving multiple organs. While the majority of genetic variants linked to ID are de novo, inherited variants are also detected in some forms. Here, we report a consanguineous Lebanese family presenting with an autosomal recessive syndromic ID characterized by neurodevelopmental delay, mild dysmorphic features, hearing impairment and endocrine dysfunction. Whole exome sequencing enabled the detection of the homozygous nonsense mutation in BOD1, p.R151X, in the proband. BOD1 is required for chromosomes biorientation during cell division. It also contributes to the regulation of cell survival and to the modulation of fatty acid metabolism. Another nonsense mutation in BOD1 was linked to ID in a consanguineous Iranian family. This is the second report of BOD1 mutations in humans and the first in a syndromic ID including gonadal dysfunction and high-frequency hearing impairment. Our findings confirm the involvement of BOD1 in cognitive functioning and expand the clinical spectrum of BOD1 deficiency.

Double homozygous Cystic Fibrosis Transmembrane Regulator gene (CFTR) mutation: A case series and review of the literature

Double homozygous mutation with the presence of double mutations in each allele is a very rare phenomenon with only 2 reports that have described this phenomenon in the medical literature.