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Background Primary ciliary dyskinesia (PCD) is a highly heterogeneous genetic disorder caused by defects in motile cilia. The hallmark features of PCD are the chronic infections of the respiratory tract, moreover, clinical manifestations include also laterality defects and risk of male infertility. Clinical phenotypes of PCD are the result of mutations in genes encoding components of axonema or factors involved in axonemal assembly. Recent studies have identified over 45 PCD-associated genes, therefore, molecular analysis represents a powerful diagnostic tool to confirm and uncover new genetic causes of this rare disease. Case presentation Here, we describe a female infant of Moroccan origin with normal pressure hydrocephalus (NPH) in addition to most common PCD symptoms. Transmission Electron Microscopy (TEM) and molecular tests, such as a Next generation Sequencing panel and a custom array CGH, were performed for diagnosis of PCD. TEM revealed outer dynein arm (ODA) defects, whilst molecular analyses detected a novel 6,9 kb microdeletion in DNAI2 gene. Conclusions Since DNAI2 mutations are very rare, this case report contributes to better delineate the important role of DNAI2 as causative of PCD phenotype, suggesting, furthermore, that the variations in DNAI2 may be as a new genetic risk factor for NPH. Indeed, although the association of hydrocephalus with PCD has been well documented, however, only a small number of human patients show this defect. Furthermore, this study highlights the importance of high-throughput technologies in advancing our understanding of heterogeneous genetic disorders.

Background and objectives: Otoferlin is a multi-C2 domain protein implicated in neurotransmitter-containing vesicle release and replenishment of the cochlear inner hair cell (IHC) synapses. Mutations in the OTOF gene have been associated with two different clinical phenotypes: a prelingual severe-to-profound sensorineural hearing loss (ANSD-DFNB9); and the peculiar temperature-sensitive auditory neuropathy (TS-ANSD), characterized by a baseline mild-to-moderate hearing threshold that worsens to severe-to-profound when the body temperature rises that returns to a baseline a few hours after the temperature has fallen again. The latter clinical phenotype has been described only with a few OTOF variants with an autosomal recessive biallelic pattern of inheritance. Case report: A 7-year-old boy presented a picture compatible with TS-ANSD exacerbated by febrile states or physical exercise with mild-to-moderate hearing loss at low and medium frequencies and a decrease in speech discrimination that worsened with an unfavorable speech-to-noise ratio. Otoacoustic emissions (OAEs) were present whereas auditory brainstem responses (ABRs) evoked by a click or tone-burst were generally absent. No inner ear malformations were described from the CT scan or MRI. Next-generation sequencing (NGS) of the known deafness genes and multi-phasic bioinformatic analyses of the data detected in OTOF a c.2521G>A missense variant and the deletion of 7.4 Kb, which was confirmed by array-comparative genomic hybridization (array-CGH). The proband’s parents, who were asymptomatic, were tested by Sanger sequencing and the father presented the c.2521G>A missense variant. Conclusions: The picture presented by the patient was compatible with OTOF-induced TS-ANSD. OTOF has been generally associated with an autosomal recessive biallelic pattern of inheritance; in this clinical report, two pathogenic variants never previously associated with TS-ANSD were described.

Background Leigh Syndrome (LS, OMIM 256000) is an early-onset, progressive neurodegenerative disorder characterized by broad clinical and genetic heterogeneity; it is the most frequent disorder of mitochondrial energy production in children. LS inheritance is complex because patients may present mutations in mitochondrial DNA (mtDNA) or in nuclear genes, which predominantly encode proteins involved in respiratory chain structure and assembly or in coenzyme Q10 biogenesis. However, during the last 15 years, the discovery of several genetic mutations and improved knowledge of the natural history of LS has significantly increased our understanding of this mitochondrial disorder. Case presentation Here we describe a 19-year-old male with clinical and neuroimaging LS diagnosed at 3 years of age. Genetic analyses of the whole mtDNA for maternally inherited LS (MILS) and neuropathy ataxia retinitis pigmentosa (NARP) syndrome failed to reveal any pathogenic mutations. Conclusions Recently, a missense mutation in ECHS1 and a ~ 35 kb deletion in 10q26.3 involving the region including the gene were identified by WES (whole exome sequencing), uncovering the genetic diagnosis clinically hypothesized for 15 years. We also report the long-term follow-up of this patient, showing a comparison with classical LS or other Leigh-like pictures.

Here, we report on a patient with a 625 kb duplication in Xp22.12, detected by array comparative genomic hybridization (CGH). The duplicated region contains only one gene, RPS6KA3, that results in partial duplication. The same duplication was present in his mother and his maternal uncle. This partial duplication inhibits the RPS6KA3 expression, mimicking the effect of loss-of-function mutations associated with Coffin-Lowry syndrome (CLS). The phenotype of the patient here presented is not fully evocative of this syndrome because he does not present some of the facial, digital and skeletal abnormalities that are considered the main diagnostic features of CLS. This case is one of the few examples where RPS6KA3 mutations are associated with a non-specific X-linked mental retardation.

ObjectivePrimary ciliary dyskinesia (PCD) severity has been related to genotype and levels of nasal nitric oxide (nNO). The most common TAS2R38 haplotypes (PAV/PAV, PAV/AVI, AVI/AVI) encoding the bitter taste receptor can affect nNO levels and thus could play a role in the susceptibility to respiratory infections. We assessed the impact of these polymorphisms on nNO production and Pseudomonas aeruginosa (P.a.) infections in different PCD genotypes.MethodsProspective, longitudinal, single-centre study in patients with PCD with known genotype and one of three TAS2R38 haplotypes evaluated for up to 10 years. We related nNO values to TAS2R38 haplotypes in all patients, and in the three most frequent genotypes (CCDC39/CCDC40, DNAH5, DNAH11). In the genetic group(s) with different mean trends of nNO in relation to the polymorphism, we evaluated longitudinal lung function as a clinical outcome measure. We also studied any associations between the prevalence of chronic P.a. infection and PAV alleles. Linear mixed-effects models were used to evaluate longitudinal associations.Results119 patients with PCD underwent 1116 study visits. Only in the DNAH11 mutations group was there a mean trend of nNO production which was significantly higher in PAV/PAV than AVI/AVI haplotype (p=0.033), with a better trend in spirometric and plethysmographic parameters. In patients with DNAH11 mutations the PAV allele was also associated with a significantly reduced prevalence of chronic P.a. infection.ConclusionTAS2R38 may be a modifier gene for PCD severity, but only in mild phenotype disease. Further study of TAS2R38 polymorphisms might enable new management strategies to prevent chronic P.a. infections.

22q11.2 is a region prone to chromosomal rearrangements due to the presence of eight large blocks of low-copy repeats (LCR22s). The 3 Mb 22q11.2 “typical deletion”, between LCR22-A and D, causes a fairly well-known clinical picture, while the effects of smaller CNVs harbored in this interval are still to be fully elucidated. Nested deletions, flanked by LCR22B-D, LCR22B-C, or LCR22C-D, are very rare and are collectively described as “central deletions”. The LCR22C-D deletion (CDdel) has never been separately analyzed. In this paper, we focused only on CDdel, evaluating its gene content and reviewing the literature and public databases in order to obtain new insights for the classification of this CNV. At first glance, CDdels are associated with a broad phenotypic spectrum, ranging from clinically normal to quite severe phenotypes. However, the frequency of specific clinical traits highlights that renal/urinary tract abnormalities, cardiac defects, and neurological/behavioral disorders are much more common in CDdel than in the general population. This frequency is too high to be fortuitous, indicating that CDdel is a predisposing factor for these phenotypic traits. Among the genes present in this interval, CRKL is an excellent candidate for cardiac and renal defects. Even if further data are necessary to confirm the role of CDdels, according to our review, this CNV fits into the class of ‘likely pathogenic’ CNVs.

We report a case of DiGeorge-like syndrome in which immunodeficiency coexisting with juvenile idiopathic arthritis, congenital heart disease, delay in emergence of language and in motor milestones, feeding and growing problems, enamel hypoplasia, mild skeletal anomalies, and facial dysmorphisms are associated with no abnormalities found on genetic tests.

Disorders of sexual development (DSDs) encompass a group of congenital conditions associated with atypical development of internal and external genital structures. Among those with DSDs are 46,XX males, whose condition mainly arises due to the translocation of SRY onto an X chromosome or an autosome. In the few SRY-negative 46,XX males, overexpression of other pro-testis genes or failure of pro-ovarian/anti-testis genes may be involved, even if a non-negligible number of cases remain unexplained. A three-year-old boy with an SRY-negative 46,XX karyotype showed a normal male phenotype and normal prepubertal values for testicular hormones. A heterozygous de novo in tandem duplication of 50,221 bp, which encompassed exons 2 and 3 of the Doublesex and Mab-3-related transcription factor 1 (DMRT1) gene, was detected using MPLA, CGH-array analysis, and Sanger sequencing. Both breakpoints were in the intronic regions, and this duplication did not stop or shift the coding frame. Additional pathogenic or uncertain variants were not found in a known pro-testis/anti-ovary gene cascade using a custom NGS panel and whole genome sequencing. The duplication may have allowed DMRT1 to escape the transcriptional repression that normally occurs in 46,XX fetal gonads and thus permitted the testicular determination cascade to switch on. So far, no case of SRY-negative 46,XX DSD with alterations in DMRT1 has been described.

Neurodevelopmental disorders (NDDs) are considered synaptopathies, as they are due to anomalies in neuronal connectivity during development. DLG2 is a gene involved insynaptic function; the phenotypic effect of itsalterations in NDDs has been underestimated since few cases have been thoroughly described.We report on eight patients with 11q14.1 imbalances involving DLG2, underlining its potential effects on clinical presentation and its contribution to NDD comorbidity by accurate neuropsychiatric data collection. DLG2 is a very large gene in 11q14.1, extending over 2.172 Mb, with alternative splicing that gives rise to numerous isoforms differentially expressed in brain tissues. A thorough bioinformatic analysis of the altered transcripts was conducted for each patient. The different expression profiles of the isoforms of this gene and their influence on the excitatory–inhibitory balance in crucial brain structures could contribute to the phenotypic variability related to DLG2 alterations. Further studies on patients would be helpful to enrich clinical and neurodevelopmental findings and elucidate the molecular mechanisms subtended to NDDs.

The clinical expression of 22q11.2 deletion syndrome (22q11.2 DS) is extremely variable, as patients can present with recurrent or severe infections, immune dysregulation, atopic diseases, or extra-immunological manifestations. The immunological background underlying the different disease manifestations is not completely elucidated. The aim of this study was to identify the immunophenotypic peculiarities of 22q11.2 DS patients presenting with different disease expressions. This study included 34 patients with 22q11.2 DS, divided into three groups according to the clinical phenotype: isolated extra-immunological manifestations (G1), infectious phenotype with increased/severe infections (G2), and immune dysregulation (G3). The patients underwent extended immunophenotyping of the T and B lymphocytes and analysis of the circulating dendritic cells (DCs). In patients with an infectious phenotype, a significant reduction in CD3+ and CD4+ cells and an expansion of CD8 naïve cells was evidenced. On the other hand, the immunophenotype of the patients with immune dysregulation showed a skewing toward memory T cell populations, and reduced levels of recent thymic emigrants (RTEs), while the highest levels of RTEs were detected in the patients with isolated extra-immunological manifestations. This study integrates the current literature, contributing to elucidating the variability in the immune status of patients with 22q11.2DS with different phenotypic expressions, particularly in those with infectious phenotype and immune dysregulation.