María Ángeles Mori

Comparative study of three diagnostic approaches (FISH, STRs and MLPA) in 30 patients with 22q11.2 deletion syndrome.

The 22q11.2 deletion syndrome is commonly diagnosed using fluorescence in situ hybridization (FISH) with commercial probes. The chromosomal breakpoints and deletion size are subsequently characterized by short tandem repeat (STR) segregation tests or by further FISH probes. Recently, a multiplex ligation‐dependent probe amplification (MLPA) single tube assay was developed to detect deletions of the 22q11.2 region and other chromosomal regions associated with DiGeorge/velocardiofacial syndrome. We have compared the results of these three techniques in a group of 30 patients affected with 22q11.2 deletion syndrome. MLPA correctly called all patients who had been previously diagnosed by FISH. The MLPA results were concordant in all patients with the STR analysis in respect to deletion size. Furthermore, this novel technique resolved seven cases that were undetermined by STR analysis. These results confirm the efficiency of MLPA as a rapid, reliable, economical, high‐throughput method for the diagnosis of 22q11.2 deletion syndrome.

Macrocephaly–capillary malformation: Analysis of 13 patients and review of the diagnostic criteria

Macrocephaly–capillary malformation (M‐CM) is a genetic syndrome of unknown etiology characterized by an enlarged head circumference and patchy, reticular capillary malformation. We describe the clinical features of 13 cases, report on the genome‐wide Copy Number Variation characterization of these patients, analyze the main clinical features of this syndrome and propose a modification of the current diagnostic criteria: the inclusion of both overgrowth/asymmetry and neuroimaging alterations as major criteria.

A prenatally diagnosed patient with full monosomy 21: ultrasound, cytogenetic, clinical, molecular, and necropsy findings.

We report on a patient with a full monosomy 21 (FM21) prenatally diagnosed in cord fetal blood, and subsequently confirmed in other tissues. Subtle chromosomal translocations of chromosome 21, were ruled‐out by FISH using both painting and 21q telomeric probes. Microsatellites analysis demonstrated the paternal origin of the single chromosome. The propositus showed at 32 weeks of gestation a severe intrauterine growth retardation and microcephaly. He was born with multiple congenital malformations, hypotonia, microcephaly, bilateral microphthalmia (more severe on the left), facial dysmorphism, agenesis of the external auditory meatus, redundant skin in the neck, narrow chest, flat scrotum, cryptorchydism, hypospadias, micropene, camptodactyly, nail hypoplasia, and abnormal palmar and plantar creases. The patient died in the first day of life. At necropsy, micrencephaly, semilobar holoprosencephaly, polimicrogyria, ocular abnormalities, skeletal anomalies, congenital heart disease, and agenesis of right kidney were also observed. To our best knowledge, this case is one of the most completely patient studied with FM21.

New microdeletion and microduplication syndromes: a comprehensive review

Several new microdeletion and microduplication syndromes are emerging as disorders that have been proven to cause multisystem pathologies frequently associated with intellectual disability (ID), multiple congenital anomalies (MCA), autistic spectrum disorders (ASD) and other phenotypic findings. In this paper, we review the “new” and emergent microdeletion and microduplication syndromes that have been described and recognized in recent years with the aim of summarizing their main characteristics and chromosomal regions involved. We decided to group them by genomic region and within these groupings have classified them into those that include ID, MCA, ASD or other findings. This review does not intend to be exhaustive but is rather a quick guide to help pediatricians, clinical geneticists, cytogeneticists and/or molecular geneticists.

Autosomal recessive hydrocephalus due to aqueduct stenosis: report of a further family and implications for genetic counselling

We report on two abortuses with hydrocephalus due to congenital stenosis of the aqueduct of Silvius. The occurrence of this disorder in two siblings (a male and a female) with normal parents supports the autosomal recessive pattern of inheritance. Such a mechanism of inheritance should be taken into account when counselling families with congenital hydrocephaly due to aqueduct stenosis.

A New Overgrowth Syndrome is Due to Mutations in RNF125.

Overgrowth syndromes (OGS) are a group of disorders in which all parameters of growth and physical development are above the mean for age and sex. We evaluated a series of 270 families from the Spanish Overgrowth Syndrome Registry with no known OGS. We identified one de novo deletion and three missense mutations in RNF125 in six patients from four families with overgrowth, macrocephaly, intellectual disability, mild hydrocephaly, hypoglycemia, and inflammatory diseases resembling Sjögren syndrome. RNF125 encodes an E3 ubiquitin ligase and is a novel gene of OGS. Our studies of the RNF125 pathway point to upregulation of RIG‐I‐IPS1‐MDA5 and/or disruption of the PI3K‐AKT and interferon signaling pathways as the putative final effectors.

Direct tandem duplication in chromosome 19q characterized by array CGH.

Partial trisomy of the long arm of chromosome 19 is a rare aneusomy. Only six cases of pure duplications have been previously reported, two of which were prenatally detected. Here we describe the clinical manifestations in a 15-month-old girl with a de novo dup(19)(q12q13.2) and the application of array-based comparative genomic hybridization with a resolution of approximately 1 Mb to characterize the duplicated segment. Seven clones were found duplicated, and the size of the fragment was determined to be 10.8 Mb. The scarce number of patients reported and the difficulty of accurately defining the duplicated segment when conventional cytogenetic methods are applied hamper the delineation of a clinical phenotype for duplication of chromosome 19q. To our knowledge this is the fifth live born reported with a pure dup(19), and the first report in which the duplicated segment has been accurately characterized by means of array CGH.

The G397A (E133K) change in the AGGF1 (VG5Q) gene is a single nucleotide polymorphism in the Spanish population

Silvia Gutierrez, Luis Magano, Alicia Delicado, Marı́a A. Mori, Marı́a L. de Torres, Luis Fernández, Marı́a Palomares, Eva Fernández, Gemma R. Tarduchy, Jesús Molano, Ricardo Gracia, Isidora López Pajares, and Pablo Lapunzina* Department of Molecular Genetics, Hospital Universitario La Paz, Madrid, Spain Department of Medical Genetics, Hospital Universitario La Paz, Madrid, Spain Sequencing Unit, IBB, Madrid, Spain The Spanish Overgrowth Syndrome Registry

Analysis of invdupdel(8p) rearrangement: Clinical, cytogenetic and molecular characterization

Inverted duplication 8p associated with deletion of the short arms of chromosome 8 (invdupdel[8p]) is a relatively uncommon complex chromosomal rearrangement, with an estimated incidence of 1 in 10,000–30,000 live borns. The chromosomal rearrangement consists of a deletion of the telomeric region (8p23‐pter) and an inverted duplication of the 8p11.2–p22 region. Clinical manifestations of this disorder include severe to moderate intellectual disability and characteristic facial features. In most cases, there are also CNS associated malformations and congenital heart defects. In this work, we present the cytogenetic and molecular characterization of seven children with invdupdel(8p) rearrangements. Subsequently, we have carried out genotype–phenotype correlations in these seven patients. The majority of our patients carry a similar deletion but different size of duplications; the latter probably explaining the phenotypic variability among them. We recommend that complete clinical evaluation and detailed chromosomal microarray studies should be undertaken, enabling appropriate genetic counseling.

FOXP1-related intellectual disability syndrome: a recognisable entity

Background Mutations in forkhead box protein P1 (FOXP1) cause intellectual disability (ID) and specific language impairment (SLI), with or without autistic features (MIM: 613670). Despite multiple case reports no specific phenotype emerged so far. Methods We correlate clinical and molecular data of 25 novel and 23 previously reported patients with FOXP1 defects. We evaluated FOXP1 activity by an in vitro luciferase model and assessed protein stability in vitro by western blotting. Results Patients show ID, SLI, neuromotor delay (NMD) and recurrent facial features including a high broad forehead, bent downslanting palpebral fissures, ptosis and/or blepharophimosis and a bulbous nasal tip. Behavioural problems and autistic features are common. Brain, cardiac and urogenital malformations can be associated. More severe ID and NMD, sensorineural hearing loss and feeding difficulties are more common in patients with interstitial 3p deletions (14 patients) versus patients with monogenic FOXP1 defects (34 patients). Mutations result in impaired transcriptional repression and/or reduced protein stability. Conclusions FOXP1-related ID syndrome is a recognisable entity with a wide clinical spectrum and frequent systemic involvement. Our data will be helpful to evaluate genotype–phenotype correlations when interpreting next-generation sequencing data obtained in patients with ID and/or SLI and will guide clinical management.