Interstitial 2q24.2q24.3 Microdeletion: Two New Cases with Similar Clinical Features with the Exception of Profound Deafness.

Interstitial 2q24.2q24.3 microdeletions are rare cytogenetic aberrations associated with heterogeneous clinical features depending on the size of the deletion.

Neurodevelopmental Disorders in Patients With Complex Phenotypes and Potential Complex Genetic Basis Involving Non-Coding Genes, and Double CNVs.

Neurodevelopmental disorders (NDDs) are a heterogeneous class of brain diseases, with a complex genetic basis estimated to account for up to 50% of cases. Nevertheless, genetic diagnostic yield is about 20%. Array-comparative genomic hybridization (array-CGH) is an established first-level diagnostic test able to detect pathogenic copy number variants (CNVs), however, most identified variants remain of uncertain significance (VUS).

Expanding the phenotype associated with interstitial 6p25.1p24.3 microdeletion: a new case and review of the literature.

Interstitial 6p25.1p24.3 microdeletions are rare events and a clear karyotype/phenotype correlation has not yet been determined.

1p31.1 microdeletion including only NEGR1 gene in two patients.

Neuronal growth regulator 1 (NEGR1), a member of the immunoglobulin superfamily cell adhesion molecule subgroup IgLON, has been involved in neuronal growth and connectivity. Genetic variants, in or near the NEGR1 locus, have been associated with obesity and, more recently, with learning difficulties, intellectual disability, and psychiatric disorders. Here, we described the only second report of NEGR1 gene disruption in 1p31.

'Distal 16p12.2 microdeletion' in a patient with autosomal recessive deafness-22.

The 16p12.2 chromosome band contains three large segmental duplications: BP1, BP2 and BP3, providing a substrate for recombination and recurrent chromosomal rearrangements. The '16p12.

Small interstitial 9p24.3 deletions principally involving KANK1 are likely benign copy number variants.

A small heterozygous deletion involving KANK1 was originally reported in 2005 to cause cerebral palsy in one large Israeli family of Jewish Moroccan origin. There were nine affected children over two generations to five unaffected fathers. All of these children had congenital hypotonia that evolved into spastic quadriplegia over the first year of life, along with intellectual impairment and brain atrophy.

Familial ROBO1 deletion associated with ectopic posterior pituitary, duplication of the pituitary stalk and anterior pituitary hypoplasia.

Background The genetic causes of abnormal pituitary development have been extensively studied in the last few years. ROBO1 is involved in neurogenesis and axon guidance. Loss-of-function variants in ROBO1 have been associated with pituitary stalk interruption syndrome (PSIS), suggesting that its haploinsufficiency could impair the guidance of hypothalamic axons to the pituitary gland leading to developmental abnormalities.

Clinical and Molecular Characterization of Two Patients with CNTN6 Copy Number Variations.

Submicroscopic chromosomal alterations usually involve different protein-coding genes and regulatory elements that are responsible for rare contiguous gene disorders, which complicate the understanding of genotype-phenotype correlations. Chromosome band 3p26.3 contains 3 genes encoding neuronal cell adhesion molecules: CHL1, CNTN6, and CNTN4.

Loss of tubulin deglutamylase CCP1 causes infantile-onset neurodegeneration.

A set of glutamylases and deglutamylases controls levels of tubulin polyglutamylation, a prominent post-translational modification of neuronal microtubules. Defective tubulin polyglutamylation was first linked to neurodegeneration in the () mouse, which lacks deglutamylase CCP1, displays massive cerebellar atrophy, and accumulates abnormally glutamylated tubulin in degenerating neurons. We found biallelic rare and damaging variants in the gene encoding CCP1 in 13 individuals with infantile-onset neurodegeneration and confirmed the absence of functional CCP1 along with dysregulated tubulin polyglutamylation.

Intragenic duplication of KCNQ5 gene results in aberrant splicing leading to a premature termination codon in a patient with intellectual disability.

The KCNQ5 gene, widely expressed in the brain, encodes a voltage-gated potassium channel (Kv7.5) important for neuronal function. Here, we report a novel KCNQ5 intragenic duplication at 6q13 spanning about 239 Kb of genomic DNA, identified by array comparative genomic hybridization (array-CGH).

Intragenic Microdeletion of ULK4 and Partial Microduplication of BRWD3 in Siblings with Neuropsychiatric Features and Obesity.

ULK4 and BRWD3 deletions have been identified in patients with developmental/language delay and intellectual disability. Both genes play pivotal roles in brain development. In particular, ULK4 encodes serine/threonine kinases that are critical for the development and function of the nervous system, while BRWD3 plays a crucial role in ubiquitination, as part of the ubiquitin/proteasome system.

3q29 microduplication syndrome: Description of two new cases and delineation of the minimal critical region.

Heterogeneous clinical and neuropsychological features, such as intellectual disability, developmental and language delay, hypotonia, and, to a lesser extent, microcephaly that is present in about the half of the reported patients, characterize the 3q29 microduplication syndrome with usually a milder phenotype compared with the corresponding 3q29 microdeletion syndrome. The duplications described so far range from 2.3 Mb to 1.

Characterization of the Phenotype Associated with Microduplication Reciprocal to NF1 Microdeletion Syndrome.

17q11.2 microduplication syndrome is a recently described relatively rare condition associated with a nonspecific phenotype. Intellectual disability, developmental delay, and dysmorphisms are the only clinical features common to a majority of cases.

Assessment of copy number variations in 120 patients with Poland syndrome.

Background: Poland Syndrome (PS) is a rare congenital disorder presenting with agenesis/hypoplasia of the pectoralis major muscle variably associated with thoracic and/or upper limb anomalies. Most cases are sporadic, but familial recurrence, with different inheritance patterns, has been observed. The genetic etiology of PS remains unknown.

Interstitial 18q22.3q23 deletion: clinical, neuroradiological and molecular characterization of a new case and review of the literature.

Background: Deletions of the long arm of chromosome 18 cause a common autosomal syndrome clinically characterized by a protean clinical phenotype.

Case Presentation: We report on a 16-month-old male infant affected by fever attacks apparently unrelated with any infectious or inflammatory symptoms, growth retardation, bilateral vertical talus, congenital aural atresia, dysmorphisms, mild psychomotor delay, and peculiar neuroradiological features. Array-CGH analysis revealed one of the smallest 18q22.

Interstitial 11q24 deletion: a new case and review of the literature.

We describe a 19-month-old male presenting with right stenotic megaureter, anemia and thrombocytopenia, cardiac and ophthalmologic abnormalities. Analysis with array-based comparative genomic hybridization (aCGH) revealed an interstitial deletion of about 2.4 Mb of chromosome 11q24.

Interstitial 9p24.3 deletion involving only DOCK8 and KANK1 genes in two patients with non-overlapping phenotypic traits.

Chromosome 9p deletion represents a clinically and genetically heterogeneous condition characterized by a wide spectrum of phenotypic manifestations and a variable size of the deleted region. The deletion breakpoint occurs from 9p22 to 9p24 bands, and the large majority of cases have either terminal deletions or translocations involving another chromosome. Here we report on two patients with similar inherited interstitial 9p24.

Thrombocytopenia-absent radius (TAR) syndrome due to compound inheritance for a 1q21.1 microdeletion and a low-frequency noncoding RBM8A SNP: a new familial case.

Background: Thrombocytopenia-absent radius syndrome (TAR; MIM 274000) is a rare autosomal recessive disorder combining specific skeletal abnormalities with a reduced platelet count. TAR syndrome has been associated with the compound inheritance of an interstitial microdeletion in 1q21.1 and a low frequency noncoding RBM8A SNP.

Clinical and Molecular Cytogenetic Characterization of a de novo Interstitial 1p31.1p31.3 Deletion in a Boy with Moderate Intellectual Disability and Severe Language Impairment.

Interstitial 1p deletions are rare events. Very few cases of 1p31.1p31.

Clinical and molecular characterization of a patient with interstitial 6q21q22.1 deletion.

Background: Interstitial 6q deletions, involving the 6q15q25 chromosomal region, are rare events characterized by variable phenotypes and no clear karyotype/phenotype correlation has been determined yet.

Results: We present a child with a 6q21q22.1 deletion, characterized by array-CGH, associated with developmental delay, intellectual disability, microcephaly, facial dysmorphisms, skeletal, muscle, and brain anomalies.

Clinico-radiological and molecular characterization of a child with ring chromosome 2 presenting growth failure, microcephaly, kidney and brain malformations.

Background: Ring chromosome 2 is a rare constitutional abnormality that generally occurs de novo. About 14 cases have been described to date, but the vast majority of papers report exclusively conventional cytogenetic investigations and only two have been characterized by array-CGH.

Results: Here we describe the clinical, neuroradiological, and molecular features of a 5-year-old boy harbouring a ring chromosome 2 presenting with severe growth failure, facial and bone dysmorphisms, microcephaly, and renal malformation.

Concomitant deletion of chromosome 16p13.11 and triplication of chromosome 19p13.3 in a child with developmental disorders, intellectual disability, and epilepsy.

Background: Rare copy number variations (CNVs) are today recognized as an important cause of various neurodevelopmental disorders, including mental retardation and epilepsy. In some cases, a second CNV may contribute to a more severe clinical presentation.

Results: Here we describe a patient with epilepsy, mental retardation, developmental disorders, and dysmorphic features, who inherited a deletion of 16p13.

Association of achondroplasia with sagittal synostosis and scaphocephaly in two patients, an underestimated condition?

We report on two patients with an unusual combination of achondroplasia and surgically treated sagittal synostosis and scaphocephaly. The most common achondroplasia mutation, p.Gly380Arg in fibroblast growth factor receptor 3 (FGFR3), was detected in both patients.