Microcephaly, epilepsy, and neonatal diabetes due to compound heterozygous mutations in IER3IP1: Insights into the natural history of a rare disorder

Neonatal diabetes mellitus is known to have over 20 different monogenic causes. A syndrome of permanent neonatal diabetes along with primary microcephaly with simplified gyral pattern associated with severe infantile epileptic encephalopathy was recently described in two independent reports in which disease-causing homozygous mutations were identified in the immediate early response-3 interacting protein-1 (IER3IP1) gene. We report here an affected male born to a non-consanguineous couple who was noted to have insulin-requiring permanent neonatal diabetes, microcephaly, and generalized seizures. He was also found to have cortical blindness, severe developmental delay and numerous dysmorphic features. He experienced a slow improvement but not abrogation of seizure frequency and severity on numerous anti-epileptic agents. His clinical course was further complicated by recurrent respiratory tract infections and he died at 8years of age. Whole exome sequencing was performed on DNA from the proband and parents. He was found to be a compound heterozygote with two different mutations in IER3IP1: p.Val21Gly (V21G) and a novel frameshift mutation p.Phe27fsSer*25. IER3IP1 is a highly conserved protein with marked expression in the cerebral cortex and in beta cells. This is the first reported case of compound heterozygous mutations within IER3IP1 resulting in neonatal diabetes. The triad of microcephaly, generalized seizures, and permanent neonatal diabetes should prompt screening for mutations in IER3IP1. As mutations in genes such as NEUROD1 and PTF1A could cause a similar phenotype, next-generation sequencing approaches-such as exome sequencing reported here-may be an efficient means of uncovering a diagnosis in future cases

Analysis of large versus small dogs reveals three genes on the canine X chromosome associated with body weight, muscling and back fat thickness

International audienceDomestic dog breeds display significant diversity in both body mass and skeletal size, resulting from intensive selective pressure during the formation and maintenance of modern breeds. While previous studies focused on the identification of alleles that contribute to small skeletal size, little is known about the underlying genetics controlling large size. We first performed a genome-wide association study (GWAS) using the Illumina Canine HD 170,000 single nucleotide polymorphism (SNP) array which compared 165 large-breed dogs from 19 breeds (defined as having a Standard Breed Weight (SBW) >41 kg [90 lb]) to 690 dogs from 69 small breeds (SBW ≤41 kg). We identified two loci on the canine X chromosome that were strongly associated with large body size at 82–84 megabases (Mb) and 101–104 Mb. Analyses of whole genome sequencing (WGS) data from 163 dogs revealed two indels in the Insulin Receptor Substrate 4 (IRS4) gene at 82.2 Mb and two additional mutations, one SNP and one deletion of a single codon, in Immunoglobulin Superfamily member 1 gene (IGSF1) at 102.3 Mb. IRS4 and IGSF1 are members of the GH/IGF1 and thyroid pathways whose roles include determination of body size. We also found one highly associated SNP in the 5’UTR of Acyl-CoA Synthetase Long-chain family member 4 (ACSL4) at 82.9 Mb, a gene which controls the traits of muscling and back fat thickness. We show by analysis of sequencing data from 26 wolves and 959 dogs representing 102 domestic dog breeds that skeletal size and body mass in large dog breeds are strongly associated with variants within IRS4, ACSL4 and IGSF1

Diagnosis and management of Silver–Russell syndrome: first international consensus statement

This Consensus Statement summarizes recommendations for clinical diagnosis, investigation and management of patients with Silver–Russell syndrome (SRS), an imprinting disorder that causes prenatal and postnatal growth retardation. Considerable overlap exists between the care of individuals born small for gestational age and those with SRS. However, many specific management issues exist and evidence from controlled trials remains limited. SRS is primarily a clinical diagnosis; however, molecular testing enables confirmation of the clinical diagnosis and defines the subtype. A 'normal' result from a molecular test does not exclude the diagnosis of SRS. The management of children with SRS requires an experienced, multidisciplinary approach. Specific issues include growth failure, severe feeding difficulties, gastrointestinal problems, hypoglycaemia, body asymmetry, scoliosis, motor and speech delay and psychosocial challenges. An early emphasis on adequate nutritional status is important, with awareness that rapid postnatal weight gain might lead to subsequent increased risk of metabolic disorders. The benefits of treating patients with SRS with growth hormone include improved body composition, motor development and appetite, reduced risk of hypoglycaemia and increased height. Clinicians should be aware of possible premature adrenarche, fairly early and rapid central puberty and insulin resistance. Treatment with gonadotropin-releasing hormone analogues can delay progression of central puberty and preserve adult height potential. Long-term follow up is essential to determine the natural history and optimal management in adulthood

Expanding the clinical spectrum of SLC29A3 gene defects.

Contains fulltext : 88665.pdf (publisher's version ) (Closed access)H syndrome and pigmented hypertrichosis with insulin dependent diabetes (PHID) are allelic autosomal recessive syndromes reported in the last year to be caused by mutations in the SLC29A3 gene, which encodes the equilibrative nucleoside transporter hENT3. Herein, we report three new patients from a single family who present with phenotypes that associate features of both PHID and H syndrome. Genetic analysis of the SLC29A3 gene revealed that two affected sisters are compound heterozygotes for the previously reported mutations p.G427S and p.G437R, while their nephew was homozygous for the p.G437R mutation. In addition to this intra-familial genetic heterogeneity, these patients demonstrate considerable phenotypic variability. One sister had clinical features consistent with classical PHID phenotype, while her nephew's features were in keeping with the diagnosis of H syndrome. The second sister displayed the most severe phenotype which combined diagnostic features from both syndromes. This patient also had features not described previously, including severe seronegative polyarthritis involving large and small joints, and hypogonadotropic hypogonadism. These manifestations may be additional characteristics of the growing clinical spectrum of SLC29A3 defects. This report emphasizes the complex genotype phenotype correlation in SLC29A3 disorders and suggests that other factors are relevant to disease manifestations and severity