The c.7409G>A (p.Cys2470Tyr) Variant of FBN1: Phenotypic Variability across Three Generations.

Marfan syndrome is an autosomal dominant connective tissue disorder caused by mutations in the fibrillin gene FBN1, which encodes an extracellular matrix glycoprotein. Major features of Marfan syndrome occur in the ocular, cardiovascular, and skeletal systems as well as in the dura mater. Approximately 60% of known disease-causing mutations are missense mutations of single amino acid residues. Effects on the cardiovascular system are classically associated with mutations in exons 24-32 of the 65 FBN1 exons and many, though not all, reports associate missense mutations in exons 59-65 with a mild cardiovascular phenotype. Here we present 5 related individuals among whom a c.7409G>A (p.Cys2470Tyr) missense variant in exon 59 of FBN1 is associated with significant cardiovascular features. The index case also had an apparently de novo 46,XX,del(5)(q33.1q33.3) deletion on chromosome 5. This family demonstrates skeletal, dermatological and neurological features consistent with Marfan syndrome but lacks significant ophthalmological findings to date. These findings suggest that FBN1 C-terminal missense mutations may not confer the ophthalmological features of Marfan syndrome, but they also confer a more significant risk for cardiovascular pathology than that suggested by previous studies. Furthermore, clinical data from this family supports the previously reported association of dural ectasia with C-terminal mutations.

19p13.2 microduplication causes a Sotos syndrome-like phenotype and alters gene expression.

Up to 90% of individuals affected by Sotos syndrome have a pathogenic alteration of NSD1 (encodes nuclear receptor-binding Su-var, enhancer of zeste, and trithorax domain protein 1), a histone methyltransferase that functions as both a transcriptional activator and a repressor. Genomic copy number variations may also cause a Sotos-like phenotype. We evaluated a three-generation family segregating a Sotos-like disorder characterized by typical facial features, overgrowth, learning disabilities, and advanced bone age. Affected individuals did not have a detectable NSD1 mutation, but rather were found to have a 1.9 Mb microduplication of 19p13.2 with breakpoints in two highly homologous Alu elements. Because the duplication included the DNA methyltransferase gene (DNMT1), we assessed DNA methylation of peripheral blood and buccal cell DNA and detected no alterations. We also examined peripheral blood gene expression and found evidence for increased expression of genes within the duplicated region. We conclude that microduplication of 19p13.2 is a novel genomic disorder characterized by variable neurocognitive disability, overgrowth, and facial dysmorphism similar to Sotos syndrome. Failed compensation of gene duplication at the transcriptional level, as seen in peripheral blood, supports gene dosage as the cause of this disorder.

Co-occurrence of Joubert syndrome and Jeune asphyxiating thoracic dystrophy.

Ciliary disorders share typical features, such as polydactyly, renal and biliary cystic dysplasia, and retinitis pigmentosa, which often overlap across diagnostic entities. We report on two siblings of consanguineous parents and two unrelated children, both of unrelated parents, with co-occurrence of Joubert syndrome and Jeune asphyxiating thoracic dystrophy, an association that adds to the observation of common final patterns of malformations in ciliary disorders. Using homozygosity mapping in the siblings, we were able to exclude all known genes/loci for both syndromes except for INVS, AHI1, and three genes from the previously described Jeune locus at 15q13. No pathogenic variants were found in these genes by direct sequencing. In the third child reported, sequencing of RPGRIP1L, ARL13B, AHI1, TMEM67, OFD1, CC2D2A, and deletion analysis of NPHP1 showed no mutations. Although this study failed to identify a mutation in the patients tested, the co-occurrence of Joubert and Jeune syndromes is likely to represent a distinct entity caused by mutations in a yet to be discovered gene. The mechanisms by which certain organ systems are affected more than others in the spectrum of ciliary diseases remain largely unknown.

A patient with vertebral, cognitive and behavioural abnormalities and a de novo deletion of NRXN1alpha.

The authors report a patient with mild mental retardation, autistic features, multiple vertebral malformations, and an unusual facial appearance who carries a de novo submicroscopic deletion of chromosome 2p16.3. The patient's deletion is approximately 320 kb in size and includes only the part of the NRXN1 gene that codes for the neurexin1alpha promoter and initial coding exons. The more downstream neurexin1beta promoter and the region surrounding it are intact. Neurexin1beta has been associated with autism in several recent studies, but this is the first reported patient with loss of only neurexin1alpha and not of neurexin1beta. These findings suggest that neurexin1alpha function in correct dosage is necessary for normal neurological development.

Heart defects and other malformations in the Inuit in Canada: a baseline study.

OBJECTIVES: Birth defects occur in all ethnic groups, remaining an important world-wide cause of perinatal and infant morbidity. This contributes greatly to an excess of health care dollars allocated to the care and repair of those affected. This is especially true when those affected live in remote geographical locations. STUDY DESIGN: A chart review of 2567 live births of children of Inuit parents residing in Arctic Quebec (Nunavik) and on Baffin Island (Nunavut) between 1989 and 1994 (five years) was carried out compared to rates of anomalies of the Alberta Congenital Anomalies Surveillance System (ACASS). RESULTS: Birth defects were higher in the Inuit sample in nearly every major ICD-9 category with the exception of neural tube defects, eye anomalies and chromosome abnormalities. (Total: 99.7/1000 Vs 51.5/1000; OR 1.93 95% CI 1.7-2.3). Congenital heart defects were significantly increased 22.9/1000 Vs 5.6/1000, with an OR of 4.18 (95% CI 3.2-5.4) in the ICD-9 category 745. In particular, ventricular septal defects (VSDs) and atrial septal defects (ASDs) (OR 4.9 CI 3.5-6.9 and 4.6 CI 2.9-7.2) were frequent. CONCLUSIONS: A high rate of heart defects was an important contributor to the nearly two times rate of total birth defects in the Inuit compared to the ACASS. Further study should be carried out to determine the contributing factors. Genetic predisposition to specific heart defects, and a diet low in folate and vitamin A are considerations. The use of alcohol may exacerbate vitamin status in pregnancy. Optimizing vitamin status in the periconceptional period may reduce the rate of birth defects.

Translocation (Y;22) resulting in the loss of SHOX and isolated short stature.

Chromosomal rearrangements involving both chromosome Y and chromosome 22 are rare, and may result in a number of different phenotypes. We report on a 4-year-old child with short stature and a dicentric chromosome with a deletion of the distal end of chromosome Yp. The pregnancy was uneventful, until intra-uterine growth retardation was noted. Prenatal karyotyping showed a (Y;22) translocation. No structural fetal abnormality was shown at ultrasound examination, and the pregnancy went to term. A growth-retarded boy with an otherwise normal physical examination was delivered at 39 weeks. At age 4, the child had short stature (-3 SD) without mental retardation. Radiological examination of the wrist was normal. A blood karyotype confirmed the chromosomal rearrangement previously seen on the amniotic fluid cells. C-banding showed a dicentric chromosome, and fluorescence in situ hybridization (FISH) with centromeric probes confirmed the presence of both chromosome Y and 22 centromeres on the derivative chromosome. The karyotype was thus 45,X,der(Y;22)(p11;q11)del(Y)(p11p11). Our patient's phenotype and chromosomal rearrangement prompted us to further investigate the distal Yp region. FISH using a subtelomeric probe showed a deletion of the distal Yp region. This technique also revealed that this chromosomal rearrangement resulted in the deletion of SHOX but not SRY. Although haploinsufficiency of SHOX may result in Léri-Weill Dyschondrosteosis, this diagnosis did not seem obvious in this young patient. This observation confirms the importance of FISH in the investigation of chromosomal abnormalities, and further delineates the phenotype of SHOX deleted patients.

[Isolated antenatal pyelic dilatation: postnatal follow-up and care for vesico-ureteral reflux]. / Dilatations pyéliques isolées: diagnostic prénatal, suivi postnatal et prise en charge des reflux vésico-urétéraux.

OBJECTIVE: To assess the risk of aneuploidia in case of isolated antenatal pyelic dilatation and to detail urological care for these children. METHODS: Prenatal and postnatal follow-up was analyzed in 350 cases. RESULTS: The overall rate of chromosome anomalies was 1.3%. Trisomy 21 was found alone in one case (0.3%). The sex ratio was 26% girls and 74% boys. Vesico-ureteral reflux was similar in both sexes (13%). CONCLUSION: The question of proposing karyotyping in case of isolated pyelic dilatation remains unsolved because minimal subjective signs such as slightly excessive amniotic fluid can completely change the assessment of the risk of aneuploidia. The frequency of postnatal vesico-ureteral reflux associated with prenatal pyelic dilatation warrants complete prenatal ultrasound screening.

Reassessment of childhood B-lineage lymphoblastic leukemia karyotypes using spectral analysis.

We studied a stratified cohort of 51 childhood B-lineage acute lymphoblastic leukemias (B-ALLs) to evaluate the efficiency of spectral karyotyping (SKY) in the detection of chromosome aberrations previously diagnosed using chromosome banding and/or reverse transcriptase polymerase chain reaction. Despite the small number of cases analyzed, several important features emerge from the study: (a) The result of banding analysis was revised in two-thirds of the cases. Eighty-three chromosome anomalies previously undetected or not characterized using chromosome banding were identified by spectral karyotyping, even in patients with apparently normal karyotypes. (b) All hyperdiploidy cases showed one or more extra copies of chromosomes X, 14, and 21. (c) Two hidden rearrangements, a t(7;12)(?p12;p13), and a new translocation, a t(9;12)(q31;p13), both involving the TEL gene, were characterized. (d) Some cryptic rearrangements, such as the der(21) t(12;21) translocation, remained undetected. (e) No new recurrent chromosome anomalies were discovered with this technique. In conclusion, the present study confirms the efficiency of the SKY technique in resolving and characterizing many complex chromosome anomalies seen in childhood B-ALLs, but it raises questions about the ability of this technique to detect cryptic rearrangements, such as the t(12;21) translocation.

[Clinical spectrum of prenatal tetralogy of Fallot]. / Spectre clinique de la tétralogie de Fallot anténatale.

The aim of this study of 44 cases of tetralogy of Fallot was to assess the echocardiographic aspects and the prognosis with respect to associated abnormalities and the potential evolution in utero. Group I, tetralogy of Fallot with other abnormalities (N = 27: 2 valvular agenesis, 26.5 5.3 weeks), had genetic anomalies in 18 of the foetus (10 trisomies including 5 trisomy 21, 5 structural abnormalities including 2 micro-deletions 22q11 in the two cases of valvular agenesis, and one deletion of chromosome 8p23.1, 3 mendelian syndromes) and other abnormalities in 9 cases. Hypoplasia of the pulmonary artery was present in 60% of cases with a non-dilated aorta in 72%, infundibular hypertrophy in 33% and 2 evolutions to pulmonary atresia. Aspect of "isolated" ventricular septal defect were observed in 20% of cases. Survival was 10%. In Group II, tetralogy of Fallot was isolated (N = 17, including 2 pulmonary valve agenesis, 31 +/- 6 weeks) (p < 0.01 versus Group I). Pulmonary artery hypoplasia was observed in 50% of cases with dilatation of the aorta and infundibular hypertrophy in all and in one a postnatal progression towards pulmonary atresia. A correlation between growth of the pulmonary artery and gestational age was found in 5 foetus out of 9 studied sequentially (p between 0.03 and 0.007) and between age at first surgery and size of the pulmonary artery (r = 0.80, p = 0.001). Survival was 84%. The risk of malformation (61%) and the prenatal potential evolution of this disease justifies continuous follow-up of all cases of tetralogy of Fallot, high resolution karyotyping and postnatal evaluation in a specialized centre.

Phenotypic manifestation in a child with 46,X,der(X)t(X;1)(q24;q31.1).

We report on a 5-year-old girl with multiple congenital anomalies, developmental delay, and a de novo unbalanced translocation between chromosomes X and 1[46,X,der(X)-t(X;1)(q24;q31.1)] resulting in partial trisomy 1q and partial monosomy Xq. The karyotype shows inactivation of the abnormal X chromosome. The translocated portion of 1q remains active in the tissues studied. This is the third case report with partial trisomy 1q and partial monosomy Xq. However, it is the first with specific breakpoints at 1q31.1 and Xq24.

Trisomy of chromosome 10 in two cases of ovarian carcinoma.

Simple numerical chromosome aberrations have been observed in tumorigenesis and may point to indicative initiating or early events in tumorigenesis. We have identified two cases of ovarian carcinomas with trisomy of chromosome 10 using conventional GTG-banding and fluorescence in situ hybridization. This is, to our knowledge, the first report of trisomy 10 as a simple karyotypic abnormality observed in ovarian carcinoma. These results suggest that further studies investigating whether chromosome 10 genes are associated with the pathogenesis of some ovarian tumors are warranted.

Cytogenetic aspects of the Canadian early and mid-trimester amniotic fluid trial (CEMAT).

Cytogenetic results from a large multicentre randomized controlled study of 2108 amniotic fluids obtained at 11+0-12+6 weeks (EA) and 1999 fluids at 15+0-16+6 weeks (MA) were compared. There was no statistically significant difference in the rate of chromosome abnormalities (EA =1.9 per cent; MA=1.7 per cent) or level III mosaicism (EA=0.2 per cent; MA= 0.2 per cent) between the groups. Level I and Level II mosaicism occurred more frequently in MA. Maternal cell contamination was not significantly different between the groups, but maternal cells only were analysed from one bloody EA fluid. The number of repeat amniocenteses because of cytogenetic problems was 2.2 per cent in the EA group compared with only 0.3 per cent in the MA group. On average, culture of EA fluids required one day more than MA fluids. Although both culture success (97.7 per cent) and accuracy (99.8 per cent) were high for patients randomized to the EA group, routine amniocentesis prior to 13 weeks' gestation is not recommended for clinical reasons including an increased risk of fetal loss and talipes equinovarus.

Spastic paraplegia, optic atrophy, microcephaly with normal intelligence, and XY sex reversal: a new autosomal recessive syndrome?

Two female sibs of first cousin Iranian parents were found to have the syndrome of spastic paraplegia, optic atrophy with poor vision, microcephaly, and normal cognitive development. Karyotype analysis showed a normal female constitution in one and a male constitution (46,XY) in the other. The XY female showed normal female external genitalia, normal uterus and tubes, and streak gonads. SRY gene sequencing was normal. We conclude that the present family probably represents a new autosomal recessive trait of pleiotropic effects including XY sex reversal and adds further evidence for the heterogeneity of spastic paraplegia syndromes as well as sex reversal syndromes.

Bone dysplasias: an introduction.

Although individual bone dysplasias are rare, as a group they are relatively common and have a significant effect on morbidity and mortality at all ages. In this brief introduction, radiologic classification, diagnosis and differential diagnosis are given. The radiologic diagnosis is emphasized, since distinction among the various bone dysplasias is based largely on radiographic findings. Prenatal diagnosis relies heavily on high-resolution real-time ultrasonography of the fetus. Precise antenatal ultrasonographic diagnosis of a bone dysplasia may be very difficult; however, accurate differentiation of a lethal versus a nonlethal anomaly is relatively easy. There has been a recent explosion of knowledge about the genetic basis of skeletal dysplasias. Collagen gene mutations have been found to be responsible for osteogenesis imperfecta and many other bone dysplasias. The locations of the genes implicated in achondroplasia and some other chondrodysplasias are now known. Histologic analysis of the growth plate may also provide specific diagnostic features in achondroplasia and other bone dysplasias. A team approach is mandatory for the diagnosis and management of this fascinating and challenging group of diseases.

Deletion of 22q11 in two brothers with different phenotype.

We have studied two brothers with submicroscopic 22q11 deletion. One brother had findings suggestive of DiGeorge syndrome, while the other had milder anomalies, including polydactyly. Fluorescence in situ hybridization (FISH) showed a minor cell line with deletion 22q11 in the mother. To our knowledge, this is the first report of a deletion of 22q11 in two sibs with different phenotypes and apparent maternal mosaicism detected with FISH. This family illustrates the variability of the syndrome and further demonstrates the possibility of gonadal mosaicism for a microdeletion. Prenatal diagnosis may be offered after the birth of a child with a 22q11 deletion, even in the absence of parental chromosomal anomalies.

Fetus with Casamassima-Morton-Nance syndrome and an inherited (6;9) balanced translocation.

We report on a fetus with cranio-facial anomalies, a narrow thorax, imperforate anus with cloacal cyst, and a genitourinary malformation with absent uterus, vagina, and external genitalia. Major thoracic defects were seen on roentgenographic examination, including absent vertebrae and ribs, a supernumerary vertebra, a hemivertebra, and rib fusion. These findings are compatible with Casamassima-Morton-Nance syndrome. The patient was the carrier of a translocation t(6;9)(p12;q12), inherited from the mother. Although the occurrence of this rearrangement may be coincidental, it may also indicate a possible locus for this autosomal recessive thoracic dysplasia.

Prenatal diagnosis for inborn errors of metabolism and haemoglobinopathies: the Montreal Children's Hospital experience.

We reviewed all referrals for prenatal diagnosis for inborn errors of metabolism and haemoglobinopathies performed at the Montreal Children's Hospital Prenatal Diagnosis Centre/McGill University during the period 1990-1995; 92 procedures were performed for these indications (less than 1 per cent of all referrals for prenatal diagnosis). All prenatal diagnoses for haemoglobinopathies (n = 55) were exclusively DNA-based. The three most frequent referrals were for beta-thalassaemia, sickle cell anaemia, and Tay-Sachs disease, accounting for 68 per cent of cases; the other indications were predominantly for untreatable inborn errors of metabolism. Our unit maintains population-based carrier screening programmes in high schools for beta-thalassaemia and Tay-Sachs diseases. Carriers detected in these programmes accounted for the majority of referrals for these two conditions. This study indicates that carrier testing and screening for sickle cell anaemia may be also welcomed by at-risk groups in Quebec.