Autosomal recessive variations of TBX6, from congenital scoliosis to spondylocostal dysostosis.

Proximal 16p11.2 microdeletions are recurrent microdeletions with an overall prevalence of 0.03%. In patients with segmentation defects of the vertebra (SDV), a burden of this microdeletion was observed with TBX6 as a candidate gene for SDV. In a published cohort of patients with congenital scoliosis (CS), TBX6 haploinsufficiency was compound heterozygous with a common haplotype. Besides, a single three-generation family with spondylocostal dysostosis (SCD) was reported with a heterozygous stop-loss of TBX6. These observations questioned both on the inheritance mode and on the variable expressivity associated with TBX6-associated SDV. Based on a national recruitment of 56 patients with SDV, we describe four patients with variable SDV ranging from CS to SCD associated with biallelic variations of TBX6. Two patients with CS were carrying a proximal 16p11.2 microdeletion associated with the previously reported haplotype. One patient with extensive SDV was carrying a proximal 16p11.2 microdeletion associated with a TBX6 rare missense change. One patient with a clinical diagnosis of SCD was compound heterozygous for two TBX6 rare missense changes. The three rare variants were affecting the chromatin-binding domain. Our data illustrate the variable expressivity of recessive TBX6 ranging from CS to SCD.

Search for ReCQL4 mutations in 39 patients genotyped for suspected Rothmund-Thomson/Baller-Gerold syndromes.

Three overlapping conditions, namely Rothmund-Thomson (RTS), Baller-Gerold (BGS) and RAPADILINO syndromes, have been attributed to RECQL4 mutations. Differential diagnoses depend on the clinical presentation, but the numbers of known genes remain low, leading to the widespread prescription of RECQL4 sequencing. The aim of our study was therefore to determine the best clinical indicators for the presence of RECQL4 mutations in a series of 39 patients referred for RECQL4 molecular analysis and belonging to the RTS (27 cases) and BGS (12 cases) spectrum. One or two deleterious RECQL4 mutations were found in 10/27 patients referred for RTS diagnosis. Clinical and molecular reevaluation led to a different diagnosis in 7/17 negative cases, including Clericuzio-type poikiloderma with neutropenia, hereditary sclerosing poikiloderma, and craniosynostosis/anal anomalies/porokeratosis. No RECQL4 mutations were found in the BGS group without poikiloderma, confirming that RECQL4 sequencing was not indicated in this phenotype. One chromosomal abnormality and one TWIST mutation was found in this cohort. This study highlights the search for differential diagnoses before the prescription of RECQL4 sequencing in this clinically heterogeneous group. The combination of clinically defined subgroups and next-generation sequencing will hopefully bring to light new molecular bases of syndromes with poikiloderma, as well as BGS without poikiloderma.

Clinical, cytogenetic and molecular characterization of two cases of mosaic ring chromosome 13.

The occurrence of mosaic ring chromosome 13 is rare. The mechanism of ring chromosome formation is usually associated with loss of genetic material. We report 2 cases of mosaic ring chromosome 13, resulting in deletion of 13qter. The first patient, a 15 year-old boy, presented a delayed psychomotor development, mental retardation, dysmorphic features and bleeding disorders associated with a de novo terminal 13q34 deletion. The second case was a foetus of 31 weeks with prenatal diagnosis of severe malformation such as holoprosencephaly, congenital cardiac defects, gastro-intestinal abnormalities with intrauterine growth retardation, the molecular analysis showed a de novo deletion encompassing the region 13q31.3-q34.

FOXL2 copy number changes in the molecular pathogenesis of BPES: unique cohort of 17 deletions.

Blepharophimosis Syndrome (BPES) is an autosomal dominant developmental disorder of the eyelids with or without ovarian dysfunction caused by FOXL2 mutations. Overall, FOXL2deletions represent 12% of all genetic defects in BPES. Here, we have identified and characterized 16 new and one known FOXL2 deletion combining multiplex ligation-dependent probe amplification (MLPA), custom-made quantitative PCR (qPCR) and/or microarray-based copy number screening. The deletion breakpoints could be localized for 13 out of 17 deletions. The deletion size is highly variable (29.8 kb - 11.5 Mb), indicating absence of a recombination hotspot. Although the heterogeneity of their size and breakpoints is not reflected in the uniform BPES phenotype, there is considerable phenotypic variability regarding associated clinical findings including psychomotor retardation (8/17), microcephaly (6/17), and subtle skeletal features (2/17). In addition, in all females in whom ovarian function could be assessed, FOXL2 deletions proved to be associated with variable degrees of ovarian dysfunction. In conclusion, we present the largest series of BPES patients with FOXL2 deletions and standardized phenotyping reported so far. Our genotype-phenotype data can be useful for providing a prognosis (i.e. occurrence of associated features) in newborns with BPES carrying a FOXL2 deletion.

Deletion of Xpter encompassing the SHOX gene and PAR1 region in familial patients with Leri-Weill Dyschondrosteosis syndrome.

Heterozygote deletions or mutations of pseudoautosomal 1 region (PAR1) encompassing the short stature homeobox-containing (SHOX) gene cause Leri-Weill Dyschondrosteosis (LWD), which is a dominantly inherited osteochondroplasia characterized by short stature with mesomelic shortening of the upper and lower limbs and Madelung deformity of the wrists. SHOX is expressed by both sex chromosomes in males and females and plays an important role in bone growth and development. Clinically, the LWD expression is variable and more severe in females than males due to sex differences in oestrogen levels. Here, we report two familial cases of LWD with a large Xp terminal deletion (approximately 943 kb) of distal PAR1 encompassing the SHOX gene. In addition, the proband had mental retardation which appeared to be from recessive inheritance in the family.

Precocious puberty associated with partial trisomy 18q and monosomy 11q.

We report a 10-years-old female patient with a partial trisomy 18q and monosomy 11q due to a maternal translocation. The phenotype of our proband is partially common with Jacobsen syndrome and duplication 18q but she has also some atypical anomalies such as precocious puberty, a retinal albinism and hypermetropia. Based on cytogenetics and FISH analysis, the karyotype of the proband was 46,XX,der(11)t(11;18)(q24;q13). To the best of our knowledge, this is the first report of precocious puberty associated with either dup(18q) or del(11q) syndromes.

[Hutchinson-Gilford progeria syndrome: clinical and molecular analysis in an African patient]. / Le syndrome de Hutchinson-Gilford (progèria): analyse clinique et moléculaire chez une patiente d'origine africaine.

Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare genetic disease characterized by an early onset of several clinical features including premature ageing in children. Approximately 80% of HGPS cases are caused by a de novo single-base pair substitution c.1824 C>T (GGC > GGT, p.Gly608Gly) within the exon 11 of the LMNA gene which codes for lamins A and C proteins. This mutation creates an abnormal splice donor site, leading to the formation of a truncated lamin A protein. Only a very few cases of African patients with HGPS have been reported, but none of them has been characterized at the molecular level. We report here a 12 year-old-girl African patient with HGPS, in whom the p.Gly608Gly heterozygous disease-causing mutation was found.

Dandy-Walker malformation with postaxial polydactyly: a new syndrome?

We report on two sibs with Dandy-Walker malformation and tetramelic postaxial polydactyly. We conclude that this is a new autosomal recessive syndrome.

Severe Smith-Lemli-Opitz syndrome with prolonged survival and lipid abnormalities.

We have studied a girl with multiple congenital anomalies, growth and mental deficiency, characteristic facial anomalies, cataracts, cerebellar atrophy, and severe hypocholesterolemia. Death occurred at age 7 years. After excluding several syndromes, i.e., peroxisomal disorders, mevalonic acidaemia, and Marinesco-Sjögren syndrome, it is concluded that this girl had severe Smith-Lemli-Opitz Syndrome (SLOS) with exceptionally long survival. This diagnosis was confirmed through assay of 7-dehydrocholesterol in cultured fibroblasts.

Familial occurrence of Summitt syndrome or a variant example of Carpenter syndrome?

In this report, we describe three sibs presenting an identical malformation syndrome i.e.: acrocephaly, brachydactyly, prominent metopic ridge, broad depressed nasal bridge, narrow maxillae, obesity and normal intelligence. We discuss the relationship between this combination of clinical signs and symptoms most compatible with the diagnosis of Summitt syndrome and the Carpenter syndrome.

Need for search for cryptic translocation in parents with several children affected with MCA: report of a cryptic translocation (10;14) detected by FISH.

The 3 affected children from 2 different wedlocks of the mother have been previously described (11). Search by FISH analysis in the mother revealed she is a carrier of balanced translocation of clear terminal G bands of equal sizes of the long arms of chromosomes 10 and 14. Chromosomal slides of the last child (Patient 3) could be analysed by fish and revealed that he did inherit the derivative chromosome 10. He had a partial trisomy 14 and a partial deletion of the long arm of chromosome 10. The clinical pictures correspondence to the possibly abnormal karyotypes will be discussed.

IRF6 Screening of Syndromic and a priori Non-Syndromic Cleft Lip and Palate Patients: Identification of a New Type of Minor VWS Sign.

Van der Woude syndrome (VWS), caused by dominant IRF6 mutation, is the most common cleft syndrome. In 15% of the patients, lip pits are absent and the phenotype mimics isolated clefts. Therefore, we hypothesized that some of the families classified as having non-syndromic inherited cleft lip and palate could have an IRF6 mutation. We screened in total 170 patients with cleft lip with or without cleft palate (CL/P): 75 were syndromic and 95 were a priori part of multiplex non-syndromic families. A mutation was identified in 62.7 and 3.3% of the patients, respectively. In one of the 95 a priori non-syndromic families with an autosomal dominant inheritance (family B), new insights into the family history revealed the presence, at birth, of lower lip pits in two members and the diagnosis was revised as VWS. A novel lower lip sign was observed in one individual in this family. Interestingly, a similar lower lip sign was also observed in one individual from a 2nd family (family A). This consists of 2 nodules below the lower lip on the external side. In a 3rd multiplex family (family C), a de novo mutation was identified in an a priori non-syndromic CL/P patient. Re-examination after mutation screening revealed the presence of a tiny pit-looking lesion on the inner side of the lower lip leading to a revised diagnosis of VWS. On the basis of this data, we conclude that IRF6 should be screened when any doubt rises about the normality of the lower lip and also if a non-syndromic cleft lip patient (with or without cleft palate) has a family history suggestive of autosomal dominant inheritance.

[Fetal or neonatal autopsy and genetic counseling. Experience of the Human Genetic Service of Liège]. / L'autopsie foetale ou néonatale et le conseil génétique. L'expérience du Service de génétique humaine de Liège.

From January 1976 to June 1984, 308 necropsies were performed on neonates and fetuses of various gestational age, mainly coming from hospitals of the province of Liege. 41% of the necropsied infants have at least one malformation and 34% of the malformed show multiple birth defects. There were 17 anatomo-clinic diagnoses of chromosomal aberrations but only 12 cases were confirmed by caryotype, for practical or technical reasons. One third of the parents of the necropsied infants came for genetic counselling with a high recurrence risk in 13% of the advices. For further improvement of the possibilities of diagnosis, we are pleading in favour of more frequent radiological and chromosomal fetal examinations. This must lead us to better convince obstetricians and neonatologists and get more favourable practical conditions to carry out the necropsies.

[Supravalvular aortic stenosis. Autosomal dominant form of congenital cardiopathy]. / La sténose aortique supravalvulaire forme dominante autosomique de cardiopathie congénitale.

We describe a family in which two generations are affected: two brothers and one of their maternal uncles. One of their two half-sisters (same mother) is also suspected of having the same cardiopathy. This observation confirms the autosomal dominant transmission of the disease and shows its variable expressivity in the family under study.