Guillaume Jedraszak

Gain‐of‐Function Mutation in STIM1 (P.R304W) Is Associated with Stormorken Syndrome

Stormorken syndrome is a rare autosomal dominant disorder characterized by a phenotype that includes miosis, thrombocytopenia/thrombocytopathy with bleeding time diathesis, intellectual disability, mild hypocalcemia, muscle fatigue, asplenia, and ichthyosis. Using targeted sequencing and whole‐exome sequencing, we identified the c.910C > T transition in a STIM1 allele (p.R304W) only in patients and not in their unaffected family members. STIM1 encodes stromal interaction molecule 1 protein (STIM1), which is a finely tuned endoplasmic reticulum Ca2+ sensor. The effect of the mutation on the structure of STIM1 was investigated by molecular modeling, and its effect on function was explored by calcium imaging experiments. Results obtained from calcium imaging experiments using transfected cells together with fibroblasts from one patient are in agreement with impairment of calcium homeostasis. We show that the STIM1 p.R304W variant may affect the conformation of the inhibitory helix and unlock the inhibitory state of STIM1. The p.R304W mutation causes a gain of function effect associated with an increase in both resting Ca2+ levels and store‐operated calcium entry. Our study provides evidence that Stormorken syndrome may result from a single‐gene defect, which is consistent with Mendelian‐dominant inheritance.

Involvement of Interstitial Telomeric Sequences in Two New Cases of Mosaicism for Autosomal Structural Rearrangements

Mosaicism for an autosomal structural rearrangement that does not involve ring or marker chromosomes is rare. The mechanisms responsible for genome instability have not always been explained. Several studies have shown that interstitial telomeric sequences (ITSs), involved in some mosaic constitutional anomalies, are potent sources of genomic instability. Here we describe two cases of mosaicism for uncommon constitutional autosomal rearrangements, involving ITSs, identified by karyotyping and characterized by FISH and SNP‐array analysis. The first patient, a boy with global developmental delay, had a rare type of pure distal 1q inverted duplication (1q32‐qter), attached to the end of the short arm of the same chromosome 1, in approximately 35% of his cells. The second patient, a phenotypically normal man, was diagnosed as having mosaic for a balanced non‐reciprocal translocation of the distal segment of 7q (7q33qter), onto the terminal region of the short arm of a whole chromosome 12, in approximately 80% of his cells. The remaining 20% of the cells showed an unbalanced state of the translocation, with only the der(7) chromosome. He was ascertained through his malformed fetus carrying a non‐mosaic partial monosomy 7q, identified at prenatal diagnosis. We show that pan‐telomeric and subtelomeric sequences were observed at the interstitial junction point of the inv dup(1q) and of the der(12)t(7;12), respectively. The present cases and review of the literature suggest that the presence of ITSs at internal sites of the chromosomes may explain mechanisms of the patientss mosaic structural rearrangements.

A Patient With Simpson-Golabi-Behmel Syndrome, Biliary Cirrhosis and Successful Liver Transplantation

Simpson–Golabi–Behmel syndrome type 1 (SGBS1) ‐OMIM 312870‐ is a rare X‐linked inherited overgrowth syndrome caused by a loss of function mutation in the GPC3 gene. Affected patients present a variable phenotype with pre‐ and post‐natal macrosomia, distinctive facial dysmophism, organomegaly, and multiple congenital anomalies. Intellectual disability is not constant. About 10% of patients have an increased risk of developing embryonic tumors in early childhood. Only one case of biliary disease has been described so far. GPC3 is localized on Xq26. It encodes for glypican 3, a heparan sulfate proteoglycan, which among its different known roles, negatively regulates liver regeneration and hepatocyte proliferation. This report concerns a male with a SGBS1, carrier of a GPC3 pathogenic mutation, and neonatal liver disease, who developed an early biliary cirrhosis. Together with the associated risk of cancer and developmental delay, liver transplantation was discussed and then successfully performed at the age of 19 months. A hypothesis on the role of GPC3 in the patients liver disease is also proposed.

A severe prenatal presentation of Cat Eye Syndrome

Institut deGe´ne´tique Me´dicale, Hoˆpital Jeanne de Flandre, CHRU de Lille, Lille, FranceCorrespondence to Guillaume Jedraszak, MD, Laboratoire de Ge´ne´tiqueMole´culaire Me´dicale, CHU d’Amiens, Avenue R. Laennec, 80054 AmiensCedex 1, FranceTel: +33 3 22 08 71 10; fax: +33 3 22 08 71 09;e-mail: guillaumejedraszak@yahoo.frReceived 2 May 2013 Accepted 8 August 2013

Should isolated fetal ventriculomegaly measured below 12 mm be viewed as a variant of the norm? Results of a 5-year experience in a prenatal referral center

Abstract Background: Fetal ventriculomegaly (VM) is defined as lateral ventricles measured above 10 mm. Some authors believe VM <12 mm are variants of the norm and need not be addressed for referral ultrasound. Methods: A retrospective continuous cohort study of 127 confirmed fetal VM was divided into three groups after initial referral sonographic assessment: isolated VM <12 mm (group A), isolated VM ≥12 mm (group B), and VM associated with other malformations (group C). We reviewed obstetric outcome and neonate evolution after 1 month with the aim of defining a pertinent prenatal workup. Results: We reported fetal infections in all groups (p = .24) and chromosomal abnormalities only in group C (p = .41). Fetal magnetic resonance imaging (MRI) found initially undiagnosed brain abnormalities in groups B and C (12.5 and 14.1%, p < .05). Ratios of healthy children after 1 month stemming, respectively, from groups A, B, and C were 66.7, 62.5, and 20.2% (p < .05). Conclusions: Our results are in favor of a systematic referral ultrasound for every fetal VM, regardless of size, as soon as definition criterion is met. Additional paraclinical assessment (maternal serologic status for toxoplasmosis and cytomegalovirus, amniocentesis, fetal cerebral MRI) should be discussed depending on the situation.

Azoospermia and trisomy 18p syndrome: a fortuitous association? A patient report and a review of the literature

Complete, isolated trisomy of the short arm of chromosome 18 is very rare. To date, only 24 cases of trisomy 18p have been reported in the literature, making it difficult to define a potentially associated phenotype. However, the available evidence suggests that few clinical features are shared by these patients: only variable intellectual disability, variable facial dysmorphism and epilepsy are reported in a few patients. Although three inherited cases of trisomy 18p have already been reported, all were of maternal origin.We report on a patient carrying an isolated complete trisomy 18p translocated to the short arm of chromosome 14 and presenting with facial dysmorphism, mild intellectual disability and non-obstructive azoospermia.Chromosomal abnormalities are more frequent in infertile men with poor sperm quality than the general population. Both numerical and structural chromosomal aberrations have been already reported within the context of azoospermia. To our knowledge, this is the first patient with trisomy 18p to present a fertility impairment due to totally altered spermatogenesis and azoospermia. Although fertility disorders were not mentioned in the four previous reports of men with trisomy 18p, none of the latter had children. We suggest that azoospermia is a previously uncharacterized feature of trisomy 18p syndrome. We further hypothesize that two mechanisms could be responsible of the fertility impairment: a meiotic synapsis defect due to the additional 18p arm that blocks meiosis, and/or overexpression of a gene located on the 18p chromosome involved in the normal testicular development.

Clinical and molecular characterization of the 20q11.2 microdeletion syndrome: Six new patients

Interstitial microdeletions of 20q chromosome are rare, only 17 patients have been reported in the literature to date. Among them, only six carried a proximal 20q11.21‐q11.23 deletion, with a size ranging from 2.6 to 6.8 Mb. The existence of a 20q11.2 microdeletion syndrome has been proposed, based on five previously reported cases that displayed anomalies of the extremities, intellectual disability, feeding difficulties, craniofacial dysmorphism and variable malformations. To further characterize this syndrome, we report on six new patients with 20q11.2 microdeletions diagnosed by whole‐genome array‐based comparative genomic hybridization. These patient reports more precisely refined the phenotype and narrowed the minimal critical region involved in this syndrome. Careful clinical assessment confirms the distinctive clinical phenotype. The craniofacial dysmorphism consists of high forehead, frontal bossing, enophthalmos, and midface hypoplasia. We have identified a 1.62 megabase minimal critical region involved in this syndrome encompassing three genes ‐ GDF5, EPB41L1, andSAMHD1– which are strong candidates for different aspects of the phenotype. These results support that 20q11.2 microdeletion syndrome is a new contiguous gene deletion syndrome with a recognizable phenotype.

New intragenic rearrangements in non-Finnish mulibrey nanism

Prenatal growth is a complex dynamic process controlled by various genetic and environmental factors. Among genetic syndromes characterized by growth restriction, MULIBREY nanism represents a rare autosomal recessive condition presenting with severe pre‐ and post‐natal growth failure, characteristic dysmorphic features but normal neurological development. The phenotype of MULIBREY nanism is variable and overlaps with others such as the Silver‐Russell syndrome. We report here three patients in two distinct non‐Finnish families from North France who were first suspected to have Silver–Russell syndrome which failed to be confirmed on molecular analyses. Clinical features in the three patients led us to also consider the diagnosis of MULIBREY nanism. Sequencing of the TRIM37 gene showed the three patients shared a novel nonsense mutation (c.181 C>T p.Arg61*) in a heterozygous state. Quantitative fluorescent multiplex PCR identified a new deletion of exons 15 and 16 in TRIM37 in one isolated patient and another deletion of exon 9 in two siblings. Breakpoints of both the deletions were localized in Alu sequences. Given the high number of Alu repeats, which predispose to gene rearrangements, one should always consider such genetic rearrangements in the molecular diagnosis of non‐Finnish MULIBREY nanism patients. Early diagnosis of the disease would prompt careful cardiac follow up of such patients as cardiological complication is a characteristic feature of the MULIBREY nanism as described in this report.

Severe Psychomotor Delay in a Severe Presentation of Cat-Eye Syndrome

Cat-eye syndrome is a rare genetic syndrome of chromosomal origin. Individuals with cat-eye syndrome are characterized by the presence of preauricular pits and/or tags, anal atresia, and iris coloboma. Many reported cases also presented with variable congenital anomalies and intellectual disability. Most patients diagnosed with CES carry a small supernumerary bisatellited marker chromosome, resulting in partial tetrasomy of 22p-22q11.21. There are two types of small supernumerary marker chromosome, depending on the breakpoint site. In a very small proportion of cases, other cytogenetic anomalies are reportedly associated with the cat-eye syndrome phenotype. Here, we report a patient with cat-eye syndrome caused by a type 1 small supernumerary marker chromosome. The phenotype was atypical and included a severe developmental delay. The use of array comparative genomic hybridization ruled out the involvement of another chromosomal imbalance in the neurological phenotype. In the literature, only a few patients with cat-eye syndrome present with a severe developmental delay, and all of the latter carried an atypical partial trisomy 22 or an uncharacterized small supernumerary marker chromosome. Hence, this is the first report of a severe neurological phenotype in cat-eye syndrome with a typical type 1 small supernumerary marker chromosome. Our observation clearly complicates prognostic assessment, particularly when cat-eye syndrome is diagnosed prenatally.

Growth hormone deficiency and pituitary malformation in a recurrent Cat-Eye syndrome: A family report

Growth hormone deficiency affects roughly between one in 3000 and one in 4000 children with most instances of growth hormone deficiency being idiopathic. Growth hormone deficiency can also be associated with genetic diseases or chromosome abnormalities. Association of growth hormone deficiency together with hypothalamic-pituitary axis malformation and Cat-Eye syndrome is a very rare condition. We report a family with two brothers presenting with growth delay due to a growth hormone deficiency associated with a polymalformation syndrome. They both displayed pre-auricular pits and tags, imperforate anus and Duane retraction syndrome. Both parents and a third unaffected son displayed normal growth pattern. Cerebral MRI showed a hypothalamic-pituitary axis malformation in the two affected brothers. Cytogenetic studies revealed a type I small supernumerary marker chromosome derived from chromosome 22 resulting in a tetrasomy 22pter-22q11.21 characteristic of the Cat-Eye syndrome. The small supernumerary marker chromosome was present in the two affected sons and the mother in a mosaic state. Patients with short stature due to growth hormone deficiency should be evaluated for chromosomal abnormality. Family study should not be underestimated.