Pathogenic variants in E3 ubiquitin ligase RLIM/RNF12 lead to a syndromic X-linked intellectual disability and behavior disorder.

RLIM, also known as RNF12, is an X-linked E3 ubiquitin ligase acting as a negative regulator of LIM-domain containing transcription factors and participates in X-chromosome inactivation (XCI) in mice. We report the genetic and clinical findings of 84 individuals from nine unrelated families, eight of whom who have pathogenic variants in RLIM (RING finger LIM domain-interacting protein). A total of 40 affected males have X-linked intellectual disability (XLID) and variable behavioral anomalies with or without congenital malformations.

ZNF462 and KLF12 are disrupted by a de novo translocation in a patient with syndromic intellectual disability and autism spectrum disorder.

We describe a patient with a de novo balanced translocation 46,XY,t(9; 13)(q31.2; q22.1) and autism spectrum disorder, intellectual disability, a metopic craniosynostosis, a corpus callosum dysgenesis and dysmorphic facial features, most notably ptosis.

Tentative clinical diagnosis of Lujan-Fryns syndrome--A conglomeration of different genetic entities?

The clinical diagnosis of Lujan-Fryns syndrome (LFS) comprises X-linked intellectual disability (XLID) with marfanoid habitus, distinct combination of minor facial anomalies and nasal speech. However the definition of syndrome was significantly broadened since the original report and implies ID with marfanoid habitus. Mutations of three genes (MED12, UPF3B, and ZDHHC9) have been reported in "broadly defined" LFS.

X-exome sequencing of 405 unresolved families identifies seven novel intellectual disability genes.

X-linked intellectual disability (XLID) is a clinically and genetically heterogeneous disorder. During the past two decades in excess of 100 X-chromosome ID genes have been identified. Yet, a large number of families mapping to the X-chromosome remained unresolved suggesting that more XLID genes or loci are yet to be identified.

Syndromes presenting adducted thumb with/without clubfoot and Dundar syndrome.

Congenital adducted thumb has been called variously as congenital clasped thumb, thumb in palm deformity or flexion adduction deformity of the thumb. This condition can be an isolated anomaly or associated with several genetic disorders. The syndromes that include adducted thumb as a cardinal feature such as Dundar Syndrome are few in the literature.

Evidence for increased SOX3 dosage as a risk factor for X-linked hypopituitarism and neural tube defects.

Genomic duplications of varying lengths at Xq26-q27 involving SOX3 have been described in families with X-linked hypopituitarism. Using array-CGH we detected a 1.1 Mb microduplication at Xq27 in a large family with three males suffering from X-linked hypopituitarism.

Congenital High Airway Obstruction Syndrome (CHAOS) as part of Fraser syndrome: ultrasound and autopsy findings.

Congenital High Airway Obstruction Syndrome (CHAOS) is a potential lethal condition. We describe a case report of CHAOS, with additional malformations diagnosed at 20 weeks. Autopsy findings are suggestive for Fraser syndrome (cryptophthalmos-syndactyly syndrome; OMIM 219000).

A prospective study of the clinical utility of prenatal chromosomal microarray analysis in fetuses with ultrasound abnormalities and an exploration of a framework for reporting unclassified variants and risk factors.

Purpose: To evaluate the clinical utility of chromosomal microarrays for prenatal diagnosis by a prospective study of fetuses with abnormalities detected on ultrasound.

Methods: Patients referred for prenatal diagnosis due to ultrasound anomalies underwent analysis by array comparative genomic hybridization as the first-tier diagnostic test.

Results: A total of 383 prenatal samples underwent analysis by array comparative genomic hybridization.

A comparative study on culture conditions and routine expansion of amniotic fluid-derived mesenchymal progenitor cells.

Background: Amniotic fluid (AF) cell populations will be applied in perinatology. We aimed to test the feasibility of large-scale cell expansion.

Study Methods: We determined the best out of three published expansion protocols for mesenchymal progenitors (AF samples, n = 4) in terms of self-renewal ability.

Identification of dosage-sensitive genes in fetuses referred with severe isolated congenital diaphragmatic hernia.

Objective: Congenital diaphragmatic hernia (CDH) is a fetal abnormality affecting diaphragm and lung development with a high mortality rate despite advances in fetal and neonatal therapy. CDH may occur either as an isolated defect or in syndromic form for which the prognosis is worse. Although conventional karyotyping and, more recently, chromosomal microarrays support a substantial role for genetic factors, causal genes responsible for isolated CDH remain elusive.

The mitochondrial solute carrier SLC25A5 at Xq24 is a novel candidate gene for non-syndromic intellectual disability.

Loss-of-function mutations in several different neuronal pathways have been related to intellectual disability (ID). Such mutations often are found on the X chromosome in males since they result in functional null alleles. So far, microdeletions at Xq24 reported in males always have been associated with a syndromic form of ID due to the loss of UBE2A.

Adult monozygotic twins discordant for intra-uterine growth have indistinguishable genome-wide DNA methylation profiles.

Background: Low birth weight is associated with an increased adult metabolic disease risk. It is widely discussed that poor intra-uterine conditions could induce long-lasting epigenetic modifications, leading to systemic changes in regulation of metabolic genes. To address this, we acquire genome-wide DNA methylation profiles from saliva DNA in a unique cohort of 17 monozygotic monochorionic female twins very discordant for birth weight.

Fetal hydrometrocolpos, uterus didelphys with low vaginal and anal atresia: difficulties in differentiation from a complex cloacal malformation: a case report.

Hydrometrocolpos, occurring in approximately 1/6000 newborn girls, can be caused by a stenotic urogenital sinus, a severe cloacal malformation, but also by other conditions such as an imperforate hymen, a midline vaginal septum and vaginal atresia. The prenatal differential diagnosis of this wide spectrum of conditions is not easy and requires a multidisciplinary approach with follow-up scans and MRI to access the severity of the condition. A non-consanguineous couple was referred in the first pregnancy at 30 weeks.

NRAS Mutations in Noonan Syndrome.

Noonan syndrome is a genetically heterogeneous disorder caused by mutations in PTPN11, SOS1, RAF1 and less frequently in KRAS, NRAS or SHOC2. Here, we performed mutation analysis of NRAS and SHOC2 in 115 PTPN11, SOS1, RAF1, and KRAS mutation-negative individuals. No SHOC2 mutations were found, but we identified 3 NRAS mutations in 3 probands.

Cytogenetic and morphological analysis of early products of conception following hystero-embryoscopy from couples with recurrent pregnancy loss.

Objective: Our knowledge about miscarriages mainly concerns pregnancies of at least 8 weeks' gestation. Information about the morphology and the genetic determinants of early aborted embryos remains limited. In addition, it is known that aneuploidies account for less than half of recurrent spontaneous abortions.

Sporadic male patients with intellectual disability: contribution of X-chromosome copy number variants.

Genome-wide array comparative genome hybridization has become the first in line diagnostic tool in the clinical work-up of patients presenting with intellectual disability. As a result, chromosome X-copy number variations are frequently being detected in routine diagnostics. We retrospectively reviewed genome wide array-CGH data in order to determine the frequency and nature of chromosome X-copy number variations (X-CNV) in a cohort of 2222 sporadic male patients with intellectual disability (ID) referred to us for diagnosis.

A new syndrome: multiple congenital abnormalities and mental retardation in two brothers.

In this report we present two brothers with abnormal neurological development, hypotonia, short stature, pylorus stenosis, pectus excavatum, brachycephaly due to craniosynostosis, frontal bossing, depressed nasal bridge, high arched-wide palate, downslant palpebral fissures, low-set, large ears, thin upper lip and bilateral cryptorchidism. The brothers were born to a couple of second cousins and were the third and fourth pregnancies of the mother. The father, the mother and the eldest sibling were phenotypically and chromosomally normal.

Meiotic errors followed by two parallel postzygotic trisomy rescue events are a frequent cause of constitutional segmental mosaicism.

Structural copy number variation (CNV) is a frequent cause of human variation and disease. Evidence is mounting that somatic acquired CNVs are prevalent, with mosaicisms of large segmental CNVs in blood found in up to one percent of both the healthy and patient populations. It is generally accepted that such constitutional mosaicisms are derived from postzygotic somatic mutations.

A microdeletion proximal of the critical deletion region is associated with mild Wolf-Hirschhorn syndrome.

It is generally accepted that the facial phenotype of Wolf-Hirschhorn syndrome is caused by deletions of either Wolf-Hirschhorn critical regions 1 or 2 (WHSCR 1-2). Here, we identify a 432 kb deletion located 600 kb proximal to both WHSCR1-2 in a patient with a WHS facial phenotype. Seven genes are underlying this deletion region including FAM193a, ADD1, NOP14, GRK4, MFSD10, SH3BP2, TNIP2.

Heterozygous missense mutations in SMARCA2 cause Nicolaides-Baraitser syndrome.

Nicolaides-Baraitser syndrome (NBS) is characterized by sparse hair, distinctive facial morphology, distal-limb anomalies and intellectual disability. We sequenced the exomes of ten individuals with NBS and identified heterozygous variants in SMARCA2 in eight of them. Extended molecular screening identified nonsynonymous SMARCA2 mutations in 36 of 44 individuals with NBS; these mutations were confirmed to be de novo when parental samples were available.

De novo mutations in the actin genes ACTB and ACTG1 cause Baraitser-Winter syndrome.

Brain malformations are individually rare but collectively common causes of developmental disabilities. Many forms of malformation occur sporadically and are associated with reduced reproductive fitness, pointing to a causative role for de novo mutations. Here, we report a study of Baraitser-Winter syndrome, a well-defined disorder characterized by distinct craniofacial features, ocular colobomata and neuronal migration defect.

Oculocerebral hypopigmentation syndrome maps to chromosome 3q27.1q29.

Background: In 1967, Cross et al. [J Pediatr 1967;70:398-406] reported four siblings with intellectual disability, microcephaly, neurologic and ocular disorders, and hypopigmentation involving skin and hair. This novel entity, known as oculocerebral hypopigmentation syndrome (OCHS) or Cross syndrome (OMIM 257800), is assumed to be autosomal recessive.

A boy with classical Rubinstein-Taybi syndrome but no detectable mutation in the CREBBP and EP300 genes.

Rubinstein-Taybi syndrome (RTS) is a rare autosomal dominant genetic disorder and is characterized by mental retardation, distinctive facial features, broad and often angulated thumbs and great toes. We report on a 7 year old boy with classical Rubinstein-Taybi syndrome. His facial and clinical features were very typical, including broad thumbs with radial angulation and broad great toes.