The power of the Mediator complex-Expanding the genetic architecture and phenotypic spectrum of MED12-related disorders.

MED12 is a member of the large Mediator complex that controls cell growth, development, and differentiation. Mutations in MED12 disrupt neuronal gene expression and lead to at least three distinct X-linked intellectual disability syndromes (FG, Lujan-Fryns, and Ohdo). Here, we describe six families with missense variants in MED12 (p.(Arg815Gln), p.(Val954Gly), p.(Glu1091Lys), p.(Arg1295Cys), p.(Pro1371Ser), and p.(Arg1148His), the latter being first reported in affected females) associated with a continuum of symptoms rather than distinct syndromes. The variants expanded the genetic architecture and phenotypic spectrum of MED12-related disorders. New clinical symptoms included brachycephaly, anteverted nares, bulbous nasal tip, prognathism, deep set eyes, and single palmar crease. We showed that MED12 variants, initially implicated in X-linked recessive disorders in males, may predict a potential risk for phenotypic expression in females, with no correlation of the X chromosome inactivation pattern in blood cells. Molecular modeling (Yasara Structure) performed to model the functional effects of the variants strongly supported the pathogenic character of the variants examined. We showed that molecular modeling is a useful method for in silico testing of the potential functional effects of MED12 variants and thus can be a valuable addition to the interpretation of the clinical and genetic findings.

Running shoes and running injuries: mythbusting and a proposal for two new paradigms: 'preferred movement path' and 'comfort filter'.

In the past 100 years, running shoes experienced dramatic changes. The question then arises whether or not running shoes (or sport shoes in general) influence the frequency of running injuries at all. This paper addresses five aspects related to running injuries and shoe selection, including (1) the changes in running injuries over the past 40 years, (2) the relationship between sport shoes, sport inserts and running injuries, (3) previously researched mechanisms of injury related to footwear and two new paradigms for injury prevention including (4) the 'preferred movement path' and (5) the 'comfort filter'. Specifically, the data regarding the relationship between impact characteristics and ankle pronation to the risk of developing a running-related injury is reviewed. Based on the lack of conclusive evidence for these two variables, which were once thought to be the prime predictors of running injuries, two new paradigms are suggested to elucidate the association between footwear and injury. These two paradigms, 'the preferred movement path' and 'the comfort filter', suggest that a runner intuitively selects a comfortable product using their own comfort filter that allows them to remain in the preferred movement path. This may automatically reduce the injury risk and may explain why there does not seem to be a secular trend in running injury rates.

Mosaic trisomy 21/monosomy 21 in a living female infant.

Many autosomal monosomies are presumed to end in arrested growth in the first few mitoses, prior even to the time of implantation, with possibly some proceeding to the stage of occult abortion. The single exception may be monosomy 21, although this has been questioned, with most earlier reports of monosomy 21 recently re-interpreted as being due to an unbalanced translocation involving chromosome 21. Here we report a female infant with a mosaic trisomy 21/monosomy 21 karyotype. While the karyotype 46,XX,i(21)(q10) is detected in all metaphases investigated in lymphocytes, mosaicism with the karyotype 46,XX,i(21)(q10)[31]/45,XX, -21[12] is seen in fibroblasts from a skin biopsy. Dysmorphic facial features and multiple malformations remarkably resemble cases of monosomy 21 that have been described in the literature. This suggests a dominant phenotypic effect of loss of one chromosome 21. Detailed clinical description, results of gene dosage studies, and cytogenetic analysis will be presented.

De novostructural chromosomal imbalances: molecular cytogenetic characterization of partial trisomies.

De novo structural chromosomal imbalances represent a major challenge in modern cytogenetic diagnostics. Based solely on conventional cytogenetic techniques it may be impossible to identify the chromosomal origin of additional chromosomal material. In these cases molecular cytogenetic investigations including multicolor-FISH (M-FISH), spectral karyotyping (SKY), multicolor banding (MCB) and cenM-FISH combined with appropriate single-locus FISH probes are highly suitable for the determination of the chromosomal origin and fine characterization of derivative chromosomes. Here we report on four patients with de novo chromosomal imbalances and distinct chromosomal phenotypes, three of them harboring pure partial trisomies: a mildly affected boy with pure partial trisomy 10q22.2-->q22.3 approximately 23.1 due to an interstitial duplication, a girl with pure trisomy 12p11.21-->pter and atypically moderate phenotype as the consequence of an X;autosome translocation, and a girl with multiple congenital abnormalities and severe developmental delay and a 46,XX,15p+ karyotype hiding a trisomy 17pter-->17q11.1. The fourth patient is a girl with minor phenotypic features and mental retardation with an inverted duplication 18q10-->p11.31 combined with a terminal deletion of 18p32. The clinical pictures are compared with previously described patients with focus on long term outcome.

Unusual chromosomal mosaicism as a cause of mental retardation and congenital malformations in a familial reciprocal translocation carrier, t(17;22)(q24.2;q11.23).

Familial reciprocal translocations are generally without phenotypic effect, although there is some evidence for a small excess of mental retardation and congenital malformations (MR/CM) in children carrying familial reciprocal translocations. Possible mechanisms whereby such translocations could have a phenotypic effect include cryptic unbalanced rearrangements, uniparental disomy, and disruption of putative genes at the breakpoints, unmasking recessive alleles on the normal homologs. Mosaicism for a supernumerary derivative chromosome in a carrier of a familial reciprocal translocation has not yet been described. We report a boy presenting with MR/CM and a familial reciprocal translocation, t(17;22)(q24.2;q11.23), inherited from the mother. Cytogenetic analysis of peripheral blood lymphocytes showed a balanced karyotype in all 32 analyzed metaphase spreads. Molecular genetic analysis was consistent with biparental origin of the normal homologs. In metaphase spreads from skin fibroblasts a supernumerary chromosome was found in all 24 cells analyzed and could be identified as der(22)t(17;22)(q24.2;q11.23). Several possible segregation modes at meiosis I followed by meiosis II or postzygotic nondisjunction of the der(22) might have led to this unusual chromosomal mosaicism. We propose hidden mosaicism as a possible cause for MR/CM in patients who apparently carry a balanced familial reciprocal translocation.

Partial tetrasomy 12pter-12p12.3 in a girl with Pallister-Killian syndrome: extraordinary finding of an analphoid, inverted duplicated marker.

Cytogenetic analysis in a girl with multiple congenital anomalies indicating Pallister-Killian syndrome (PKS) showed a supernumerary marker chromosome in 1/76 lymphocytes and 34/75 fibroblast metaphases. GTG-banding pattern was consistent with the chromosomal region 12pter-12q11. While fluorescence-in-situ hybridisation (FISH) with a whole chromosome 12 painting probe confirmed the origin of the marker, a chromosome 12 specific alpha-satellite probe did not hybridise to it. FISH analysis with a specific subtelomeric probe 12p showed hybridisation to both ends of the marker chromosome. High-resolution multicolour-banding (MCB) studies revealed the marker to be a der(12)(pter-->p12.3::p12.3-->pter). Summarising the FISH information, we defined the marker as an inverted duplication of 12pter-12p12.3 leading to partial tetrasomy of chromosome 12p. In skin fibroblasts, cultured at the patient's age of 1 year and 9 years, the marker chromosome was found in similar frequencies, even after several culture passages. Therefore, we consider the marker to have a functional centromere although it lacks detectable centromeric alpha-satellite sequences. To the best of our knowledge, this is the first proven analphoid marker of chromosome 12. Molecular genetic studies indicated that this marker is of paternal origin. The finding of partial tetrasomy 12pter-12p12.3 in our PKS patient allows to narrow down the critical region for PKS.

Loss of the Y chromosomal PAR2-region in four familial cases of satellited Y chromosomes (Yqs).

Applying fluorescence in-situ hybridization (FISH) of various Y chromosomal DNA probes to four familial cases of human Yqs, it was possible to demonstrate that the formation of Yqs must have arisen from a reciprocal translocation involving the short arm of an acrocentric autosome and the heterochromatin of the long arm of the Y chromosome (Yqh). Breakpoints map within Yqh and the proximal short arm of an acrocentric autosome resulting in the gain of a nucleolus organizer region (NOR) including the telomere repeat (TTAGGG)n combined with the loss of the pseudoautosomal region 2 (PAR2) at the long arm of the recipient Y chromosome. In no case could the reciprocal product of an acrocentric autosome with loss of the NOR and gain of PAR2 be detected. Using the 15p-specific classical satellite-III probe D15Z1 in two of the four Yqs probands presented here, it could be shown that the satellited material originated from the short arm of chromosome 15. In contrast to the loss of PAR2 in Yqs chromosomes, another Y chromosomal variant (Yqh-) showing deletion of long-arm heterochromatin in Yq12 has retained PAR2 referring to an interstitial deletion of Yq heterochromatin in such deleted Y chromosomes.

Tall stature, gonadal dysgenesis, and stigmata of Turner's syndrome caused by a structurally altered X chromosome.

Genetic analysis in a tall 14-year-old girl with gonadal dysgenesis and some stigmata of Turner's syndrome revealed a duplication of the short arm in a monocentric X chromosome with partial loss of Xq. We suggest that triple gene dosage of SHOX and estrogen deficiency caused the unique overgrowth.

Retrospective diagnosis of trisomy 15 in formalin-fixed, paraffin-embedded placental tissue in a newborn girl with Prader-Willi syndrome.

Paternal deletion of 15q11-q13 and maternal uniparental disomy (UPD) of chromosome 15 are the main causes of Prader-Willi syndrome (PWS). The finding of an UPD(15) is associated with increased maternal age. We present a retrospective diagnosis of a trisomy 15 mosaicism confined to the placenta (CPM) after birth of a girl with clinical features of PWS born to a 43-year-old mother. Chromosome analysis after amniocentesis, performed because of advanced maternal age, had shown a normal female karyotype. In peripheral blood cells molecular studies showed the absence of the paternal allele at the SNRPN locus and fluorescence in situ hybridization (FISH) analysis excluded a deletion of the SNRPN locus on both chromosomes 15. Trisomic cells were detected by FISH on nuclei isolated from formalin-fixed, paraffin-embedded placental tissue using a DNA-probe specific for the centromeric region of chromosome 15.

Microdeletion 4p16.3 in three unrelated patients with Wolf-Hirschhorn syndrome.

Wolf-Hirschhorn syndrome (WHS) is a multiple malformation syndrome caused by partial monosomy of 4p16.3. Pitt-Rogers-Danks syndrome, first thought to be a distinct entity, is a similar condition associated with a microdeletion overlapping the WHS critical region. In this paper we evaluate three WHS patients showing a microdeletion of 4p and remarkable development with respect to the clinical spectrum of WHS.

A second case of inv(4)pat with both recombinants in the offspring: rec dup(4q) in a girl with Wolf-Hirschhorn syndrome and rec dup(4p).

In a girl presenting with features of Wolf-Hirschhorn syndrome, cytogenetic and molecular cytogenetic analysis revealed a rearranged chromosome 4 with monosomy of the distal bands 4pter-->4p16.2 and trisomy of the distal bands 4q35.1-->4qter [rec dup(4q)] due to a large, paternal pericentric inversion. In the following two pregnancies, prenatal diagnosis showed the same imbalance in one fetus and a reverse segmental imbalance [rec dup(4p)] in the other. We discuss the recombination risk of the given inversion with respect to the size of the inverted segment and the viability of the recombinants. The high frequency of recombinants in this family and others suggests a high recurrence risk in similar cases with large pericentric inversions comprising almost entire chromosomes.

Bilaterally cleft lip, limb defects, and haematological manifestations: Roberts syndrome versus TAR syndrome.

We report on a 13-year-old patient followed since birth. He is the only offspring of young, non-consanguineous German parents. His mother has an isolated left cleft of lip and a cleft palate. At birth, our patient presented with bilaterally cleft lip/cleft palate, phocomelia of upper limbs with normal hands, and mild symmetrical deficiencies of the long bones of the lower limbs. Haematological evaluation demonstrated a leukaemoid reaction during a urinary tract infection as well as intermittent thrombocytopenia and episodes of marked eosinophilia during the first two years of life. Intellectual development has been normal. Comparison with two similar cases from the literature suggests a non-random phenotypic overlap of Roberts syndrome (MIM 268300) and TAR syndrome (MIM 274000). Such clinical constellations may be key observations to understand the genetic relationship of Roberts syndrome and TAR syndrome in future phenotype-genotype correlations.

Molecular and cytogenetic [correction of cytogenate] analysis of an X/autosomal translocation: 45,X,dic(X;17)(p22.2;p13)

We present an unusual case of monosomy 17p13-pter and monosomy Xp22.2-pter due to a dicentric translocation chromosome X/17 in a female newborn with severe anomalies. The karyotype was identified as 45,X,dic(X;17)(p22.2;p13) by high resolution GTG banding in lymphocytes. R banding showed the translocational X-chromosome to be late replicating, and there was no spreading of X-inactivation onto the autosomal segment. Furthermore, it could be demonstrated by C banding that the X-centromere in the translocation chromosome was inactive. The results of short tandem repeat (STR) typing confirmed the partial monosomy X and 17 as well as the paternal origin of the two chromosomes X and 17 which were involved in the translocation chromosome formation. The cell stage of the structural rearrangement was consistent with paternal meiosis as well as with postzygotic mitosis. The monosomy was confirmed in lymphocytes and fibroblasts, and mosaicism was not detected.

New case of mosaic tetrasomy 9p with additional neurometabolic findings.

Tetrasomy 9p is a rare chromosomal aberration that was described in 28 previous patients. Here we report on a newborn girl who was referred for genetic evaluation because of developmental delay, hypertonicity, microcephaly, minor anomalies, and neurometabolic findings. She had an isochromosome 9p (pter --> p10 --> pter) in 32% of blood cells. The extra chromosome was not found in amniocytes. Examination of fibroblasts from different skin biopsies also showed mosaicism in this tissue. In a first biopsy from the abdominal wall, the cells (n = 50) had a normal chromosomal complement. Further analysis of fibroblasts from the left forearm showed the isochromosome 9p in 5 out of 8 mitoses. Fluorescence in situ hybridization (FISH), using a whole chromosome 9 probe, confirmed that the extra marker was 9 in origin. Molecular studies showed that the isochromosome was of maternal origin. Meiotic nondisjunction was followed by centromeric misdivision and postzygotic loss of the marker.

Molecular studies in 37 Silver-Russell syndrome patients: frequency and etiology of uniparental disomy.

We report studies on the etiology of uniparental disomy (UPD) in Silver-Russell syndrome (SRS) patients. Thirty-seven SRS families were typed with short tandem repeat markers from chromosomes 2, 7, 9, 14, and 16. UPD for these chromosomes has either been described in association with growth retardation or has been observed in confined placental mosaicism, a mechanism that may result in UPD. Maternal UPD7 was detected in three SRS patients, accounting for approximately 10% of the tested SRS patients. These results agree with previously published studies. The allelic distribution in one of the three families indicates complete isodisomy, whereas allelic patterns in the other two families are consistent with partial and complete heterodisomy, respectively, suggesting that, in the latter cases, UPD originates from maternal meiosis, whereas in the first case, it seems to be of mitotic origin. STR typing for UPD of chromosomes 2, 9, 14, and 16 showed no abnormalities. Our results demonstrate the necessity of screening SRS patients for UPD7, although the effect of UPD7 cannot be correlated with the SRS phenotype as yet. An association between UPD for the other investigated chromosomes and SRS seems to be negligible.

Restrictive dermopathy: report and review.

Restrictive dermopathy (RD) is a lethal autosomal recessive genodermatosis (MIM No. 275210) in which tautness of the skin causes fetal akinesia or hypokinesia deformation sequence (FADS). Polyhydramnios with reduced fetal movements is followed by premature delivery at around 31 weeks gestation. Manifestations include a tightly adherent, thin, translucent skin with prominent vessels, typical facial changes, generalized joint contractures, enlarged fontanelles, dysplasia of clavicles, respiratory insufficiency, and an enlarged placenta with short umbilical cord. Histologic abnormalities of the skin include thin dermis with paucity and hypoplasia of the appendages and abnormally arranged collagen bundles. Elastic fibers are nearly missing. The subcutaneous fat is slightly increased. These skin findings usually appear after 22 or 24 weeks of gestation, which is why prenatal diagnosis with skin biopsy may fail. This disease is easily differentiated from other congenital FADS, such as Pena-Shokeir syndrome, COFS syndrome, Parana hard-skin syndrome, etc. We report on an affected boy of consanguineous parents and 30 previous cases are reviewed.

Prenatal detection of double aneuploidy trisomy 10/monosomy X in a liveborn twin with exclusively monosomy X in blood.

Both double aneuploidy and trisomy 10 are rare chromosome findings. All five published cases of trisomy 10 in liveborns were found to be mosaic with an euploid cell line. In a liveborn female twin, double aneuploidy mosaicism 47,XX, + 10/45,X was detected prenatally by amniocentesis performed because of severe intrauterine growth retardation and malformations. Chromosome analysis from neonatal lymphocyte cultures revealed exclusively the 45,X cell line. Double aneuploidy mosaicism trisomy 10/monosomy X was confirmed from skin fibroblasts. The child died at the age of 7 weeks. This is the first reported case of double aneuploidy involving trisomy 10, and the first case of trisomy 10 without a normal cell line in a liveborn. Prenatal diagnosis of trisomy 10 in a liveborn has not been published so far. The case illustrates that in specific cases amniotic fluid cells may reflect the karyotype of the fetus better than blood.

Five novel mutations in the L1CAM gene in families with X linked hydrocephalus.

Five novel mutations have been identified in the gene encoding L1CAM, a neural cell adhesion protein, in families with X linked hydrocephalus (XHC). Interestingly, all five mutations are in the evolutionarily highly conserved Ig-like domains of the protein. The two frameshift mutations (52insC and 955delG) and the nonsense mutation (Trp276Ter) most probably result in functional null alleles and complete absence of L1CAM at the cell surface. The two missense mutations (Tyr194Cys and Pro240Leu) may considerably alter the structure of the L1CAM protein. These data provide convincing evidence that XHC is genetically extremely heterogeneous.