Claudia Cesaretti

Pregnancy outcome in patients with β-thalassemia intermedia at two tertiary care centers, in Beirut and Milan

β-thalassemia intermedia (TI) patients can present with a severe clinical disease at 2–6 years of age or remain asymptomatic until adult life. They suffer from mild anemia (hemoglobin (Hb) between 7–10 g/dL), and are usually transfusion independent.[1][1] Pregnancy in these women, whether

SMCHD1 mutations associated with a rare muscular dystrophy can also cause isolated arhinia and Bosma arhinia microphthalmia syndrome

Arhinia, or absence of the nose, is a rare malformation of unknown etiology that is often accompanied by ocular and reproductive defects. Sequencing of 40 people with arhinia revealed that 84% of probands harbor a missense mutation localized to a constrained region of SMCHD1 encompassing the ATPase domain. SMCHD1 mutations cause facioscapulohumeral muscular dystrophy type 2 (FSHD2) via a trans-acting loss-of-function epigenetic mechanism. We discovered shared mutations and comparable DNA hypomethylation patterning between these distinct disorders. CRISPR/Cas9-mediated alteration of smchd1 in zebrafish yielded arhinia-relevant phenotypes. Transcriptome and protein analyses in arhinia probands and controls showed no differences in SMCHD1 mRNA or protein abundance but revealed regulatory changes in genes and pathways associated with craniofacial patterning. Mutations in SMCHD1 thus contribute to distinct phenotypic spectra, from craniofacial malformation and reproductive disorders to muscular dystrophy, which we speculate to be consistent with oligogenic mechanisms resulting in pleiotropic outcomes.

126 novel mutations in Italian patients with neurofibromatosis type 1.

Genetic analysis of Neurofibromatosis type 1 (NF1) may facilitate the identification of patients in early phases of the disease. Here, we present an overview of our diagnostic research spanning the last 11 years, with a focus on the description of 225 NF1 mutations, 126 of which are novel, found in a series of 607 patients (513 unrelated) in Italy. Between 2003 and 2013, 443 unrelated patients were profiled by denaturing high pressure liquid chromatography (DHPLC) analysis of 60 amplicons derived from genomic NF1 DNA and subsequent sequencing of heterozygotic PCR products. In addition, a subset of patients was studied by multiplex ligation‐dependent probe amplification (MLPA) to identify any duplications, large deletions or microdeletions present at the locus. Over the last year, 70 unrelated patients were investigated by MLPA and sequencing of 22 amplicons spanning the entire NF1 cDNA. Mutations were found in 70% of the 293 patients studied by DHPLC, thereby fulfilling the NIH criterion for the clinical diagnosis of NF1 (detection rate: 70%); furthermore, 87% of the patients studied by RNA sequencing were genetically characterized. Mutations were also found in 36 of the 159 patients not fulfilling the NIH clinical criteria. We confirmed a higher incidence of intellectual disability in patients harboring microdeletion type 1 and observed a correlation between a mild phenotype and the small deletion c.2970_2972delAAT or the missense alteration in amino acid residue 1809 (p.Arg1809Cys). These data support the use of RNA‐based methods for genetic analysis and provide novel information for improving the management of symptoms in oligosymptomatic patients.

Neurofibromatosis type 1 and pregnancy: Maternal complications and attitudes about prenatal diagnosis

Neurofibromatosis type 1 (NF1) is one of the most commoninherited genetic disorders with an incidence of 1/2,500 to 1/3,300 live births. The disease is caused by a mutation in NF1,atumorsuppressorgeneon17q11.2codingforneurofibromin,orbyamicrodeletioninvolvingtheNF1anditssurroundingregion.NF1is an autosomal dominant condition with complete penetranceafter childhood. Almost half the cases result from a de novomutation,whiletheothersinheritthealteredgenefromanaffectedparent.Thediseaseismarkedbypoorgenotype–phenotypecorre-lation and high inter- and intra-familial variability. Thereforegenetic counseling for affected individuals is hampered by thedifficulty in forecasting the clinical outcome for future offspring.Prenatal testing can be carried out if the parental mutation isknown, or if there are multiple affected family members, andlinkagehasbeenestablishedwithinthefamily;suchtestingisusefulfor establishing the presence of the parental mutation in the fetalDNA, but, as noted, cannot make any prediction about diseaseseverity [Origone et al., 2000; Terzi et al., 2009].Pregnancyhasalwaysbeenconsideredacriticaltimeforwomenwith NF1 because of reports of increased complications duringgestationarisingfrompre-eclampsia,pretermlabor,IUGR,hyper-tension, oligohydramnios, and spontaneous abortion and/or still-birth [Blickstein and Lancet, 1987; Sharma et al.,1991;Segalet al.,1999].Furthermore,casereportsdescribedtheassociationbetweenpregnancy and HELLP syndrome [Hagymasy et al., 1998; Agarwaletal.,2003],diagnosisofmalignantperipheralnervesheathtumor(MPNST)[Posmaaetal.,2003;KelloggandWatson,2010;Nelsonet al., 2010] and the occurrence of pheochromocytoma [Liu et al.,1996]. Although Dugoff and Sujansky [1996] presented a largestudy of pregnancy in 105 women, including data from 247gestations and noted a greater cesarean rate than in thegeneral population, they did not find an increased incidence ofany of these complications. However they did describe thegrowth of new neurofibromas and the enlargement ofexistingneurofibromasinmorethanthehalf.Althoughthemajor-ity of NF1 pregnant women did not report complications, someinvestigators proposed special monitoring in specific situations[Chetty et al., 2011].Here we describe our experience in the management of preg-nancies in women with NF1, and their attitude towards prenataldiagnosis. We included 43 women with a total of 79 pregnancies.Eightofthewomen(18.6%)werereferredforcareduringtheentiregestationalperiod,whiletheother35womenhadtheirpregnanciesdetected before joining our program; for them we obtained datafrom a review of their medical records and through personalinterviews. Among these 79 pregnancies, 65 were carried to termwhile the other 14 resulted in five first trimester spontaneousabortions, seven elective terminations (not related to concernsaboutNF1),andtwotherapeuticabortionsafterprenataldiagnosisthrough chorionic villus sampling (CVS). Two of the 65 full termpregnancies were twins, for a total of 67 live births.Forwomenvisitingourcenterbeforeandduringtheirpregnan-cies, we set up a model based on a set of preconceptional multi-specializedevaluationsthatwefeltwereaprerequisiteforaproperpersonalized management of pregnancy in women with NF1. The

Autosomal Dominant Diseases are too Often Overlooked in the Parents of Affected Children: Report of Six Cases

Clinical genetics is the discipline which deals with hereditary diseases and implies a strong diagnostic approach without which all information conveyed by the counselling process has insecure foundation and the estimation of recurrence risk within the family may be misinterpreted. The ideal time for having a genetic counselling is before pregnancy. In this case the subsequent genetic evaluation and counselling may lead to the definition of a reproductive risk and thus to an early, even prenatal diagnosis in the offspring. However in some cases genetic conditions are under-recognized in the adult age and people are not referred to genetic services. This happens because of a variety of reasons both related to the health professionals (non-habit to the pre-conceptional genetic counselling, lack of attention/information on genetic themes, diagnostic difficulties related to the variability of gene expression, incomplete penetrance and late onset conditions) and to the patient’s psychological status, for example denial mechanisms. Six cases are presented in which a correct diagnosis in one parent was reached after the identification of a rare disease in the child with severe psychological and social consequences. Obviously the lack of the correct diagnosis in the parent implied that he/she was not only uninformed about the presence of the increased reproductive risk, but also unaware of the clinical variability of the condition. Anger and frustration was present in all affected parents asking why their family doctors never suspected the condition which, afterwards, seemed quite obvious. Legal actions were started in two out of six cases. Establishing the correct diagnosis, or at least the suspicion of a genetic disease, is therefore a priority that may be not considered an exclusive responsibility of the geneticist, but ideally involves other medical figures, for example primary care physician, pediatricians or other medical specialists who see a patient with a condition.

Does absolute excess of alpha chains compromise the benefit of splenectomy in patients with thalassemia intermedia

β thalassemia intermedia (TI) is a clinical definition referring to a heterogeneous group of hereditary anemias resulting from defective β chain production, an α/β globin chain imbalance, and anemia that lie in severity between that of thalassemia minor and the transfusion-dependent thalassemia

The absence that makes the difference: choroidal abnormalities in Legius syndrome

Neurofibromatosis type 1 (NF1) is an hereditary disorder characterized by abnormal proliferation of multiple tissues of neural crest origin, and presents mainly with multiple café-au-lait macules, axillary freckling and neurofibromas. Choroidal involvement in NF1 patients has been studied, thanks to the development of non-invasive tools such as infrared monochromatic light during fundus examination, which showed bright patchy lesions consistent with choroidal nodules. Choroidal abnormalities identified with near-infrared reflectance have reported with a frequency of up to 100% in NF1, and have been recently been proposed as a novel diagnostic criterion for NF1. Legius syndrome can be clinically indistinguishable from NF1 and results in a small percentage of individuals being misdiagnosed. We investigated the presence of choroidal abnormalities in Legius syndrome to determine their specificity to NF1 and their potential usefulness as a novel diagnostic criterion for NF1. We examined the fundus of 16 eyes by confocal scanning laser ophthalmoscopy with infrared monochromatic light in eight patients with molecularly confirmed Legius syndrome. No abnormalities were observed, confirming the diagnostic value of choroidal abnormalities for the diagnosis of NF1.

Partial Trisomy 13 and Partial Monosomy 8 Mosaicism Secondary to an Unbalanced De Novo Translocation Highlighting an Uncommon Chromosomal Abnormality

Few cases of mosaicism involving a normal cell line and an unbalanced autosomal translocation have been reported so far. No cases of partial trisomy 13 and partial monosomy 8 mosaicism have been published. The authors report a new patient with partial trisomy 13 and partial monosomy 8 mosaicism due to an unbalanced translocation (13/8). A postzygotic mitotic exchange of nonhomologous chromatids followed by the loss of one of the translocated chromatids has been hypothesized as the potential underlying mechanism. Although a clear correlation of the clinical features of the patient with his chromosomal abnormality can be challenging, dysmorphic features, hyperactive behavior, moderate developmental delay, and tonic-clonic seizures can be interpreted as secondary to the particular genotype of the patient. These findings should be taken into account in the diagnostic process of patients presenting with multiple congenital anomalies and/or mental retardation conditions.

Occurrence of complete arhinia in two siblings with a clinical picture of Treacher Collins syndrome negative for TCOF1, POLR1D and POLR1C mutations.

Medical Genetics Unit, Fondazione IRCCS Cà Granda, Ospedale Maggiore Policlinico, Milan, Department of Maxillo-Facial Surgery, San Paolo University Hospital, Milan and Medical Genetics Laboratory, Policlinico S. Orsola-Malpighi, Bologna, Italy Correspondence to Dr Faustina Lalatta, MD, UOD Genetica Medica, Fondazione IRCCS Cà Granda, Ospedale Maggiore Policlinico, via della Commenda 12, Milano 20122, Italy Tel: + 39 0255032150; fax: + 39 0255032353; e-mail: f.lalatta@policlinico.mi.it

Correction: The absence that makes the difference: choroidal abnormalities in Legius syndrome

Correction to: Journal of Human Genetics advance online publication 27 July 2017; https://doi.org/10.1038/jhg.2017.78