Deletion of 16q22.2q23.3 in a Boy with a Phenotype Reminiscent of Silver-Russell Syndrome

A 15-month-old boy presented with growth and global developmental delay, feeding difficulties, sleep disturbance and several minor anomalies, including a large anterior fontanel, relative macrocephaly, and a triangular face. Clinical suspicion prompted genetic investigations for Silver-Russell syndrome and related disorders. SNP array analysis led to the diagnosis of an approximately 10-Mb large deletion of the long arm in chromosome 16q22.2q23.3. Interstitial deletions of 16q show a wide variability of related features; however, considering the differences in size and location of the deletions in the known patients, the phenotypic overlap is surprising. Here, we report a novel microdeletion, compare the proband with data from scientific literature and international databases, and discuss possible diagnostic implications.

The 46, XX Ovotesticular Disorder of Sex Development With Xq27.1q27.2 Duplication Involving the SOX3 Gene: A Rare Case Report and Literature Review

Background: Very few reports are available on human XX ovotesticular disorder of sex development involving SOX3 gene duplication. Here we aim to present a rare case of SOX3 gene duplication in a person from the Chinese population who exhibits XX ovotesticular disorder of sex development.Case Presentation: A 7-year-old Chinese individual from Fujian province in Southeast China was recruited. The patient presented 46, XX karyotype, absence of sex-determining region Y, and was diagnosed with XX ovotesticular disorder of sex development. Furthermore, SNP array analysis demonstrated that the patient had a 2.2-Mb duplication in the Xq27.1q27.2 region (arr[hg19]Xq27.1q27.2:139,499,778-141,777,782) involving the SOX3 gene. Additionally, no SOX3 duplication was observed in the parents or the sibling, who displayed none of the clinical features.Conclusion: We identified the first case of SOX3 duplication in a Chinese individual who exhibits ovotesticular disorder of sex development. Our study strengthens the link between the SOX3 duplication and XX ovotesticular disorder of sex development and indicates that SOX3 is the evolutionary antecedent of sex-determining region Y.

Pathogenic convergence of CNVs in genes functionally associated to a severe neuromotor developmental delay syndrome

Background Complex developmental encephalopathy syndromes might be the consequence of unknown genetic alterations that are likely to contribute to the full neurological phenotype as a consequence of pathogenic gene combinations. Methods To identify the additional genetic contribution to the neurological phenotype, we studied as a test case a boy, with a KCNQ2 exon-7 partial duplication, by single-nucleotide polymorphism (SNP) microarray to detect copy-number variations (CNVs). Results The proband presented a cerebral palsy like syndrome with a severe motor and developmental encephalopathy. The SNP array analysis detected in the proband several de novo CNVs, nine partial gene losses (LRRC55, PCDH9, NALCN, RYR3, ELAVL2, CDH13, ATP1A2, SLC17A5, ANO3), and two partial gene duplications (PCDH19, EFNA5). The biological functions of these genes are associated with ion channels such as calcium, chloride, sodium, and potassium with several membrane proteins implicated in neural cell-cell interactions, synaptic transmission, and axon guidance. Pathogenically, these functions can be associated to cerebral palsy, seizures, dystonia, epileptic crisis, and motor neuron dysfunction, all present in the patient. Conclusions Severe motor and developmental encephalopathy syndromes of unknown origin can be the result of a phenotypic convergence by combination of several genetic alterations in genes whose physiological function contributes to the neurological pathogenic mechanism.

Pathogenic convergence of CNVs in genes functionally associated to a severe neuromotor developmental delay syndrome

Background: Complex developmental encephalopathy syndromes might be the consequence of unknown genetic alterations are likely to contribute to the full neurological phenotype as a consequence of pathogenic gene combinations. Methods: To identify the additional genetic contribution to the neurological phenotype, we studied as a test case a boy, with a KCNQ2 exon-7 partial duplication, by single nucleotide polymorphism (SNP) microarray to detect copy-number variations (CNVs). Results: The proband presented a cerebral palsy like syndrome with a severe motor and developmental encephalopathy. The SNP array analysis detected in the proband several de novo CNVs, nine partial gene losses (LRRC55, PCDH9, NALCN, RYR3, ELAVL2, CDH13, ATP1A2, SLC17A5, ANO3), and two partial gene duplications (PCDH19, EFNA5). The biological functions of these genes are associated with ion channels such as calcium, chloride, sodium, and potassium; and with several membrane proteins implicated in neural cell-cell interactions, synaptic transmission and axon guidance. Pathogenically, these functions can be associated to cerebral palsy, seizures, dystonia, epileptic crisis, and motor neuron dysfunction, all present in the patient. Conclusions: Severe motor and developmental encephalopathy syndromes of unknown origin can be the result of a phenotypic convergence by combination of several genetic alterations in genes whose physiological function contributes to the neurological pathogenic mechanism.

Homozygous HESX1 and COL1A1 Gene Variants in a Boy with Growth Hormone Deficiency and Early Onset Osteoporosis

We report on a patient born to consanguineous parents, presenting with Growth Hormone Deficiency (GHD) and osteoporosis. SNP-array analysis and exome sequencing disclosed long contiguous stretches of homozygosity and two distinct homozygous variants in HESX1 (Q6H) and COL1A1 (E1361K) genes. The HESX1 variant was described as causative in a few subjects with an incompletely penetrant dominant form of combined pituitary hormone deficiency (CPHD). The COL1A1 variant is rare, and so far it has never been found in a homozygous form. Segregation analysis showed that both variants were inherited from heterozygous unaffected parents. Present results further elucidate the inheritance pattern of HESX1 variants and recommend assessing the clinical impact of variants located in C-terminal propeptide of COL1A1 gene for their potential association with rare recessive and early onset forms of osteoporosis.

Evaluation of chromosomal abnormalities and copy number variations in fetuses with ultrasonic soft markers

Background Some ultrasonic soft markers can be found during ultrasound examination. However, the etiology of the fetuses with ultrasonic soft markers is still unknown. This study aimed to evaluate the genetic etiology and clinical value of chromosomal abnormalities and copy number variations (CNVs) in fetuses with ultrasonic soft markers. Methods Among 1131 fetuses, 729 had single ultrasonic soft marker, 322 had two ultrasonic soft markers, and 80 had three or more ultrasonic soft markers. All fetuses underwent conventional karyotyping, followed by single nucleotide polymorphism (SNP) array analysis. Results Among 1131 fetuses with ultrasonic soft markers, 46 had chromosomal abnormalities. In addition to the 46 fetuses with chromosomal abnormalities consistent with the results of the karyotyping analysis, the SNP array identified additional 6.1% (69/1131) abnormal CNVs. The rate of abnormal CNVs in fetuses with ultrasonic soft marker, two ultrasonic soft markers, three or more ultrasonic soft markers were 6.2%, 6.2%, and 5.0%, respectively. No significant difference was found in the rate of abnormal CNVs among the groups. Conclusions Genetic abnormalities affect obstetrical outcomes. The SNP array can fully complement conventional karyotyping in fetuses with ultrasonic soft markers, improve detection rate of chromosomal abnormalities, and affect pregnancy outcomes.

A Beckwith-Wiedemann Syndrome Case with de novo 24 Mb Duplication of Chromosome 11p15.5-14.3

BackgroundMolecular genetic testing for the 11p15-associated imprinting disorder Beckwith-Wiedemann syndrome(BWS) is challenging because of the molecular heterogeneity and complexity of the affected imprinted regions. An accurate diagnosis of BWS requires a complete molecular method to analyze epigenetic changes.Case presentationWe reported a Chinese case with BWS detected by SNP array analysis and methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA). The genetic analysis showed a de nove duplication of 24 Mb at 11p15.5-14.3 is much longer than ever reported. MS-MLPA showed copy number changes with a peak height ratio value of 1.5(three copies) at 11p15. The duplication of paternal origin withincrease of methylation index of 0.68 at H19 and decreased methylation index of 0.37 at KCNQ1OT1.ConclusionCombined chromosome microarray analysis and methylation profiling provided reliable diagnosis for this paternally derived duplication of BWS. The phenotype associated with 11p15 duplications depends on the size, genetic content, parental inheritance and imprinting status. Identification of these rare duplications is crucial for genetic counselling.

Pathogenic convergence of CNVs in genes functionally associated to a severe neuromotor developmental delay syndrome

Background Complex developmental encephalopathy syndromes might be the consequence of unknown genetic alterations are likely to contribute to the full neurological phenotype as a consequence of pathogenic gene combinations. Methods To identify the additional genetic contribution to the neurological phenotype, we studied as a test case a boy, with a KCNQ2 exon-7 partial duplication, by single nucleotide polymorphism (SNP) microarray to detect copy-number variations (CNVs). Results The proband presented a cerebral palsy like syndrome with a severe motor and developmental encephalopathy. The SNP array analysis detected in the proband several de novo CNVs, nine partial gene losses (LRRC55, PCDH9, NALCN, RYR3, ELAVL2, CDH13, ATP1A2, SLC17A5, ANO3), and two partial gene duplications (PCDH19, EFNA5). The biological functions of these genes are associated with ion channels such as calcium, chloride, sodium, and potassium; and with several membrane proteins implicated in neural cell-cell interactions, synaptic transmission and axon guidance. Pathogenically, these functions can be associated to cerebral palsy, seizures, dystonia, epileptic crisis, and motor neuron dysfunction, all present in the patient. Conclusions Severe motor and developmental encephalopathy syndromes of unknown origin can be the result of a phenotypic convergence by combination of several genetic alterations in genes whose physiological function contributes to the neurological pathogenic mechanism.

A novel phenotype of 13q12.3 microdeletion characterized by epilepsy in an Asian child: a case report

Background The microdeletion of chromosome 13 has been rarely reported. Here, we report a 14-year old Asian female with a de novo microdeletion on 13q12.3. Case presentation The child suffered mainly from two types of epileptic seizures: partial onset seizures and myoclonic seizures, accompanied with intellectual disability, developmental delay and minor dysmorphic features. The electroencephalogram disclosed slow waves in bilateral temporal, together with generalized spike-and-slow waves, multiple-spike-and-slow waves and slow waves in bilateral occipitotemporal regions. The exome sequencing showed no pathogenic genetic variation in the patient’s DNA sample. While the single nucleotide polymorphism (SNP) array analysis revealed a de novo microdeletion spanning 2.324 Mb, within the cytogenetic band 13q12.3. Conclusions The epilepsy may be associated with the mutation of KATNAL1 gene or the deletion unmasking a recessive mutation on the other allele, and our findings could provide a phenotypic expansion.