SOX2: Not always eye malformations. Severe genital but no major ocular anomalies in a female patient with the recurrent c.70del20 variant

SOX2 variants have been identified in multiple patients with severe ocular anomalies and pituitary dysfunction, in addition to various systemic features. We investigated a 26-year-old female patient suffering from spastic paraparesis, hypoplasia of corpus callosum, hypogonadotropic hypogonadism (HH) and intellectual disability, who was monitored for over 20 years, allowing a detailed genotype-phenotype correlation along time. Whole exome sequencing on the patient and her relatives identified a de novo SOX2 c.70del20 variant, which has been frequently reported in individuals with SOX2-related anophthalmia. Importantly, our patient lacked major ocular phenotype but showed vaginal agenesis, a feature never reported before. Although the involvement of male urogenital tract (cryptorchidism, hypospadias, small penis), is a well known consequence of SOX2 variants, their effect on the female genitalia has never been properly addressed, even considering the paradoxical female excess of SOX2 cases in the literature. Our findings emphasize the importance of testing for SOX2 variants in individuals with HH and genital anomalies even though anophthalmia or microphthalmia are not observed. Moreover, our case strengthens the role of SOX2 as a master regulator of female gonadal differentiation, as widely demonstrated for other SOX genes related to 46, XX sex reversal, such as SOX3 and SOX9

Small supernumerary marker chromosomes: a legacy of trisomy rescue?

We studied by a whole cytogenomics approach 12 de novo, non-recurrent small supernumerary marker chromosomes (sSMC), detected as mosaics during pre- or postnatal diagnosis. In 11 cases maternal age was increased. Trios genotyping, WGS, and CGH+SNP array, demonstrated that (i) four sSMCs contained pericentromeric portions only, whereas eight had additional non-contiguous portions of the same chromosome, assembled together in a disordered fashion by repair-based mechanisms in a chromothriptic event; (ii) in four cases maternal hetero/isodisomy was detected with a sharp paternal origin of the sSMC in two cases, whereas in a fifth case two maternal alleles in the sSMC region and biparental haplotypes of the homologs were detected. In five other cases the homologs were biparental while the sSMC had the same haplotype of the maternally inherited chromosome. In one case, the sSMC was of paternal origin while the homologs were biparental. These findings strongly suggest that most sSMCs are the result of a multiple-step mechanism, initiated by maternal meiotic non-disjunction followed by post-zygotic anaphase lagging of the supernumerary chromosome and its subsequent insertion within a micronucleus, whose segregation to one of the two daughter cells accounts for the mosaic condition. The sequential micronuclear shattering, re-embedding of the fragmented chromosomal material into the main nucleus where repair occurs, and loss of some fragments, explains both the disordered assembly of most sSMCs and the occurrence of maternal UPD. This mechanism identifies a link between numerical and structural chromosomal anomalies and underlines that genetic counselling in prenatally detected sSMCs will be problematic.We studied by a whole cytogenomics approach 12 de novo, non-recurrent small supernumerary marker chromosomes (sSMC), detected as mosaics during pre- or postnatal diagnosis. In 11 cases maternal age was increased. Trios genotyping, WGS, and CGH+SNP array, demonstrated that (i) four sSMCs contained pericentromeric portions only, whereas eight had additional non-contiguous portions of the same chromosome, assembled together in a disordered fashion by repair-based mechanisms in a chromothriptic event; (ii) in four cases maternal hetero/isodisomy was detected with a sharp paternal origin of the sSMC in two cases, whereas in a fifth case two maternal alleles in the sSMC region and biparental haplotypes of the homologs were detected. In five other cases the homologs were biparental while the sSMC had the same haplotype of the maternally inherited chromosome. In one case, the sSMC was of paternal origin while the homologs were biparental. These findings strongly suggest that most sSMCs are the result of a multiple-step mechanism, initiated by maternal meiotic non-disjunction followed by post-zygotic anaphase lagging of the supernumerary chromosome and its subsequent insertion within a micronucleus, whose segregation to one of the two daughter cells accounts for the mosaic condition. The sequential micronuclear shattering, re-embedding of the fragmented chromosomal material into the main nucleus where repair occurs, and loss of some fragments, explains both the disordered assembly of most sSMCs and the occurrence of maternal UPD. This mechanism identifies a link between numerical and structural chromosomal anomalies and underlines that genetic counselling in prenatally detected sSMCs will be problematic

Confini e medicina di precisione in coppie consanguinee di migranti: la ricezione della consulenza genetica successiva all'identificazione di patologie fetali

Il fenomeno migratorio porta in Italia e in Europa numerose coppie di consanguinee. Il rischio di disordini genetici nei prodotti di concepimento di queste coppie è nettamene maggiore rispetto a coppie non consanguinee. Il dato che più colpisce è la disinformazione delle coppie migrante riguardo alle conseguenze della consanguineità. Di qui la necessità di attuare un approccio sensibile alla diversità culturale per realizzare con queste coppie una comunicazione più efficace su questa delicata tematica

Insertional translocation involving an additional nonchromothriptic chromosome in constitutional chromothripsis: Rule or exception?

Background Chromothripsis, which is the local massive shattering of one or more chromosomes and their reassembly in a disordered array with frequent loss of some fragments, has been mainly reported in association with abnormal phenotypes. We report three unrelated healthy persons, two of which parenting a child with some degree of intellectual disability, carrying a chromothripsis involving respectively one, two, and three chromosomes, which was detected only after whole-genome sequencing. Unexpectedly, in all three cases a fragment from one of the chromothripsed chromosomes resulted to be inserted within a nonchromothripsed one. Methods Conventional cytogenetic techniques, paired-end whole-genome sequencing, polymerase chain reaction, and Sanger sequencing were used to characterize complex rearrangements, copy-number variations, and breakpoint sequences in all three families. Results In two families, one parent was carrier of a balanced chromothripsis causing in the index case a deletion and a noncontiguous duplication at 3q in case 1, and a t(6;14) translocation associated with interstitial 14q deletion in case 2. In the third family, an unbalanced chromothripsis involving chromosomes 6, 7, and 15 was inherited to the proband by the mosaic parent. In all three parents, the chromothripsis was concurrent with an insertional translocation of a portion of one of the chromothriptic chromosomes within a further chromosome that was not involved in the chromothripsis event. Conclusion Our findings show that (a) both simple and complex unbalanced rearrangements may result by the recombination of a cryptic parental balanced chromothripsis and that (b) insertional translocations are the spy of more complex rearrangements and not simply a three-breakpoint event

Small supernumerary marker chromosomes: A legacy of trisomy rescue?

We studied by a whole genomic approach and trios genotyping, 12 de novo, nonrecurrent small supernumerary marker chromosomes (sSMC), detected as mosaics during pre- or postnatal diagnosis and associated with increased maternal age. Four sSMCs contained pericentromeric portions only, whereas eight had additional non-contiguous portions of the same chromosome, assembled together in a disordered fashion by repair-based mechanisms in a chromothriptic event. Maternal hetero/isodisomy was detected with a paternal origin of the sSMC in some cases, whereas in others two maternal alleles in the sSMC region and biparental haplotypes of the homologs were detected. In other cases, the homologs were biparental while the sSMC had the same haplotype of the maternally inherited chromosome. These findings strongly suggest that most sSMCs are the result of a multiple-step mechanism, initiated by maternal meiotic nondisjunction followed by postzygotic anaphase lagging of the supernumerary chromosome and its subsequent chromothripsis

Chiari 1 malformation and exome sequencing in 51 trios: the emerging role of rare missense variants in chromatin‑remodeling genes

Type 1 Chiari malformation (C1M) is characterized by cerebellar tonsillar herniation of 3-5 mm or more, the frequency of which is presumably much higher than one in 1000 births, as previously believed. Its etiology remains undefined, although a genetic basis is strongly supported by C1M presence in numerous genetic syndromes associated with different genes. Whole-exome sequencing (WES) in 51 between isolated and syndromic pediatric cases and their relatives was performed after confirmation of the defect by brain magnetic resonance image (MRI). Moreover, in all the cases showing an inherited candidate variant, brain MRI was performed in both parents and not only in the carrier one to investigate whether the defect segregated with the variant. More than half of the variants were Missense and belonged to the same chromatin-remodeling genes whose protein truncation variants are associated with severe neurodevelopmental syndromes. In the remaining cases, variants have been detected in genes with a role in cranial bone sutures, microcephaly, neural tube defects, and RASopathy. This study shows that the frequency of C1M is widely underestimated, in fact many of the variants, in particular those in the chromatin-remodeling genes, were inherited from a parent with C1M, either asymptomatic or with mild symptoms. In addition, C1M is a Mendelian trait, in most cases inherited as dominant. Finally, we demonstrate that modifications of the genes that regulate chromatin architecture can cause localized anatomical alterations, with symptoms of varying degrees