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

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

International audienceBackground: Fetal ventriculomegaly (VM) is defined as lateral ventricles measured above 10mm. Some authors believe VM <12mm 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 <12mm (group A), isolated VM 12mm (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

New intragenic rearrangements in non-Finnish mulibrey nanism

International audiencePrenatal 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

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

International audienceBackground: Fetal ventriculomegaly (VM) is defined as lateral ventricles measured above 10mm. Some authors believe VM <12mm 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 <12mm (group A), isolated VM 12mm (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

Optical genome mapping, a promising alternative to gold standard cytogenetic approaches in a series of acute lymphoblastic leukemias

International audienceAcute lymphoblastic leukemias (ALL) are characterized by a large number of cytogenetic abnormalities of clinical interest that require the use of several complementary techniques. Optical genome mapping (OGM) is based on analysis of ultra-high molecular weight DNA molecules that provides a high-resolution genome-wide analysis highlighting copy number and structural anomalies, including balanced translocations. We compared OGM to standard techniques (karyotyping, fluorescent in situ hybridization, single nucleotide polymorphism-array and reverse transcription multiplex ligation-dependent probe amplification) in 10 selected B or T-ALL. Eighty abnormalities were found using standard techniques of which 72 (90%) were correctly detected using OGM. Eight discrepancies were identified, while 12 additional anomalies were found by OGM. Among the discrepancies, four were detected in raw data but not retained because of filtering issues. However, four were truly missed, either because of a low variant allele frequency or because of a low coverage of some regions. Of the additional anomalies revealed by OGM, seven were confirmed by another technique, some of which are recurrent in ALL such as LMO2-TRA and MYC-TRB fusions. Despite false positive anomalies due to background noise and a case of inter-sample contamination secondarily identified, the OGM technology was relatively simple to use with little practice. Thus, OGM represents a promising alternative to cytogenetic techniques currently performed for ALL characterization. It enables a time and cost effective analysis allowing identification of complex cytogenetic events, including those currently inaccessible to standard techniques

Optical genome mapping, a promising alternative to gold standard cytogenetic approaches in a series of acute lymphoblastic leukemias

International audienceAcute lymphoblastic leukemias (ALL) are characterized by a large number of cytogenetic abnormalities of clinical interest that require the use of several complementary techniques. Optical genome mapping (OGM) is based on analysis of ultra-high molecular weight DNA molecules that provides a high-resolution genome-wide analysis highlighting copy number and structural anomalies, including balanced translocations. We compared OGM to standard techniques (karyotyping, fluorescent in situ hybridization, single nucleotide polymorphism-array and reverse transcription multiplex ligation-dependent probe amplification) in 10 selected B or T-ALL. Eighty abnormalities were found using standard techniques of which 72 (90%) were correctly detected using OGM. Eight discrepancies were identified, while 12 additional anomalies were found by OGM. Among the discrepancies, four were detected in raw data but not retained because of filtering issues. However, four were truly missed, either because of a low variant allele frequency or because of a low coverage of some regions. Of the additional anomalies revealed by OGM, seven were confirmed by another technique, some of which are recurrent in ALL such as LMO2-TRA and MYC-TRB fusions. Despite false positive anomalies due to background noise and a case of inter-sample contamination secondarily identified, the OGM technology was relatively simple to use with little practice. Thus, OGM represents a promising alternative to cytogenetic techniques currently performed for ALL characterization. It enables a time and cost effective analysis allowing identification of complex cytogenetic events, including those currently inaccessible to standard techniques

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