Biallelic KITLG variants lead to a distinct spectrum of hypomelanosis and sensorineural hearing loss.

BACKGROUND: Pathogenic variants in KITLG, a crucial protein involved in pigmentation and neural crest cell migration, cause non-syndromic hearing loss, Waardenburg syndrome type 2, familial progressive hyperpigmentation and familial progressive hyper- and hypopigmentation, all of which are inherited in an autosomal dominant manner. OBJECTIVES: To describe the genotypic and clinical spectrum of biallelic KITLG-variants. METHODS: We used a genotype-first approach through the GeneMatcher data sharing platform to collect individuals with biallelic KITLG variants and reviewed the literature for overlapping reports. RESULTS: We describe the first case series with biallelic KITLG variants; we expand the known hypomelanosis spectrum to include a 'sock-and-glove-like', symmetric distribution, progressive repigmentation and generalized hypomelanosis. We speculate that KITLG biallelic loss-of-function variants cause generalized hypomelanosis, whilst variants with residual function lead to a variable auditory-pigmentary disorder mostly reminiscent of Waardenburg syndrome type 2 or piebaldism. CONCLUSIONS: We provide consolidating evidence that biallelic KITLG variants cause a distinct auditory-pigmentary disorder. We evidence a significant clinical variability, similar to the one previously observed in KIT-related piebaldism.

Congenital cataracts in females caused by BCOR mutations; report of six further families demonstrating clinical variability and diverse genetic mechanisms.

BACKGROUND: Pathogenic variants in the BCOR gene have been identified in males with X-linked recessive microphthalmia and in females with X-linked dominant oculofaciocardiodental (OFCD) syndrome. This latter condition has previously been regarded as rare but the increased availability of genetic testing in recent years has led to the identification of a greater number of patients. METHODS: We report the clinical and molecular findings in a series of 10 patients with pathogenic BCOR variants from 5 families, all seen in a single institution over a two year period. RESULTS: We emphasize the phenotypic variability in this cohort and the diverse genetic mechanisms involved which included point mutations and deletions of BCOR as well as the occurrence of gonadal and somatic mosaicism. CONCLUSION: In this report we demonstrate the novel findings of four newly identified variants in BCOR associated with an OFCD phenotype, and suggest that the frequency of this condition in females presenting with congenital cataract, including unilateral cataract, is more common than anticipated. We demonstrate the utility of screening for genetic causes of congenital cataract. Although gonadal mosaicism in OFCD had previously been reported, we demonstrate the presence of somatic mosaicism where BCOR mutations may only be detected in DNA from tissues other than blood such as buccal cells.

Hypoglycaemia represents a clinically significant manifestation of PIK3CA- and CCND2-associated segmental overgrowth.

The PI3K-AKT signalling cascade has a highly conserved role in a variety of processes including cell growth and glucose homoeostasis. Variants affecting this pathway can lead to one of several segmental overgrowth disorders. These conditions are genetically heterogeneous and require tailored, multidisciplinary involvement throughout life. Hypoglycaemia is common in other overgrowth syndromes but has been described only sporadically in association with PIK3CA and CCND2 variants. We report a cohort of 6 children with megalencephaly-capillary malformation (MCAP) and megalencephaly-polydactyly-polymicrogyria-hydrocephalus (MPPH) syndromes who developed clinically significant hypoglycaemia. Based on our findings, we suggest that segmental overgrowth patients should be screened for low blood glucose levels during childhood and there should be early specialist endocrine review in any children who develop hypoglycaemia.

Diagnosing the cause of bilateral paediatric cataracts: comparison of standard testing with a next-generation sequencing approach.

PurposeIn addition to environmental causes such as TORCH infection, trauma and drug or chemical exposure, childhood cataracts (CC) frequently have a genetic basis. They may be isolated or syndromic and have been associated with mutations in over 110 genes. We have recently demonstrated that next-generation sequencing (NGS), a high throughput sequencing technique that enables the parallel sequencing of multiple genes, is ideally suited to the investigation of bilateral CC. This study assesses the diagnostic outcomes of traditional routine investigations and compares this with outcomes of NGS testing.MethodsA retrospective review of the medical records of 27 consecutive patients with bilateral CC presenting in 2010-2012 was undertaken. The outcomes of routine investigations in these patients, including TORCH screen, urinalysis, karyotyping, and urinary and plasma organic amino acids, were collated. The success of routine genetic investigations undertaken over 10 years (2000-2010) was also assessed.ResultsBy April 2014, the underlying cause of bilateral CC had been identified in just one of 27 patients despite 44% (n=12) receiving a full 'standard' investigative work-up and 22% (n=6) investigations in addition to the standard work-up. Fifteen of these patients underwent NGS testing and nine (60%) of these received a diagnosis for their CC.ConclusionThe frequency of patients receiving a diagnosis for their CC after standard care and the time taken to diagnosis was disappointing. NGS testing improved diagnostic rates and time to diagnosis, as well as changing clinical management. These data serve as a baseline for future evaluation of novel diagnostic modalities.

Two patients with chromosome 22q11.2 deletion presenting with childhood obesity and hyperphagia.

Chromosome 22q11.2 deletion syndrome is a clinically heterogeneous condition of intellectual disability, parathyroid and thyroid hypoplasia, palatal abnormalities, cardiac malformations and psychiatric symptoms. Hyperphagia and childhood obesity is widely reported in Prader-Willi Syndrome (PWS) but there is only one previous report of this presentation in chromosome 22q11.2 deletion syndrome. We describe two further cases of chromosome 22q11.2 deletion syndrome in which hyperphagia and childhood obesity were the presenting features. This may be a manifestation of obsessive behaviour secondary to some of the psychiatric features commonly seen in chromosome 22q11.2 deletion syndrome. Serious complications may result from hyperphagia and childhood obesity therefore early recognition and intervention is crucial. Due to the similar clinical presentation of these two patients to patients with PWS, it is suggested that the hyperphagia seen here should be managed in a similar way to how it is managed in PWS.

Dysmorphology services: a snapshot of current practices and a vision for the future.

Dysmorphology concerns the recognition and management of rare, multiple anomaly syndromes. Genomic technologies and software for gestalt recognition will re-shape dysmorphology services. In order to reflect on a model of the service in the post-genomic era, we compared the utility of dysmorphology consultations in two Mediterranean cities, Athens, Greece and Afula, Israel (MDS), the Manchester Centre for Genomic Medicine, a UK service with dysmorphology expertise (UKDS) and the DYSCERNE, digital service (DDS). We show that it is more likely that chromosome microarray analysis will be performed if suggested in the UKDS rather than in the MDS; this, most probably reflects the difference of access to genetic testing following funding limitations in the MDS. We also show that in terms of achieved diagnosis, the first visit to a dysmorphology clinic is more significant than a follow-up. We show that a confirmed syndrome diagnosis significantly decreases the requests for other, non-genetic, laboratory investigations. Conversely, it increases the requests for reviews by other specialists and, most significantly (t-test: 8.244), it increases further requests for screening for possible associated complications. This is the first demonstration of the demands, on a health service, following the diagnosis of a dysmorphic condition.

Niemann-Pick type C disease: a novel NPC1 mutation segregating in a Greek island.

Niemann-Pick type C (NPC) disease is a rare autosomal recessive lysosomal storage disease, exhibiting an extremely heterogeneous clinical phenotype. It is a cellular lipid trafficking disorder characterized by the accumulation in the lysosomal/late endosomal system of a variety of lipids, especially unesterified cholesterol. So far two genes, NPC1 or NPC2, have been linked to the disorder. It is a panethnic disease for which two isolates have been described. We present a novel NPC1 mutation (p.A1132P; c.3394G>C) identified in homozygosity in two patients originating from the same small town of an Aegean Sea island and the results of the broad screening of their extended families. Overall 153 individuals have so far been investigated and a total of 64 carriers were identified. Moreover a common descent of the individuals tested was revealed and all carriers could be traced back to a common surname, apparently originating from a common ancestor couple six generations back. The mutation was found associated with an uncommon haplotype in the island that is also present in other populations.

Dysmorphology at a distance: results of a web-based diagnostic service.

In 2007, the DYSCERNE pilot project funded by the European Commission Public Health Executive Agency (EU DG Sanco) aimed at setting up a network of expertise for patients with rare dysmorphic disorders. As part of DYSCERNE, a Dysmorphology Diagnostic System (DDS) was set up to enable clinicians throughout the EU to submit cases electronically for diagnosis using a secure, web-based interface, hosted at specified access points (Submitting nodes), in 26 different European countries. We report the outcome of this service for 200 cases submitted consecutively between January 2010 and 2012. Each case was reviewed by an average of five expert reviewers. An average of three possible syndromic diagnoses was suggested per case. In 22.5% of the cases, a consensus clinical diagnosis was reached. Genetic testing was suggested in 70.5% of the cases, whereas other laboratory investigations and diagnostic imaging were recommended in 35.5 and 26% of the cases, respectively. Further specialized opinions were suggested in 23.5% of the cases. Overall, a total of 181 very rare or extremely rare genetic syndromes were considered in the differential diagnosis of the 200 cases. In two cases, the reviewers suggested that the findings represented a new syndrome, and in one of these syndromes the underlying genetic cause was subsequently identified. Other benefits of the submission process included the possibility of directing the case submitters to specific centres for diagnostic testing or participation in research and educational benefit derived for both case submitters and reviewers.

Neurocognitive effects of methylphenidate on ADHD children with different DAT genotypes: a longitudinal open label trial.

The variable number of tandem repeat polymorphism in the 3'-untranslated region of the dopamine transporter gene (DAT) may influence the variability of the therapeutic response to methylphenidate (MPH) in Attention Deficit/Hyperactivity Disorder (ADHD). For this reason we evaluated the neuropsychological functioning after a prolonged period of MPH treatment and after a specific time from MPH suspension. Relationship between DAT VNTR genotypes and neurocognitive response to MPH was analyzed in a sample of 108 drug-naive ADHD patients. The performance of children with ADHD on measures of working memory, inhibition and planning was assessed at 4, 8 and 24 weeks and at 8 weeks after MPH withdrawal. Patients with 9/9 genotype evidenced an improvement in response inhibition and working memory only at 4 weeks of treatment, in planning at 24 weeks of therapy and after 8 weeks of MPH suspension. Patients with 9/10 showed an improvement in response inhibition at 4, 8 and 24 weeks of treatment, in planning at 24 weeks and after 8 weeks of MPH suspension. Patients with 10/10 evidenced an improvement in response inhibition and working memory at 4, 8 and 24 weeks of treatment and in planning at 4, 8 and 24 weeks of treatment and after 8 weeks of suspension. These results indicate that the 9/9 ADHD genotype has a different response at 24 weeks treatment with MPH. 10/10 DAT allele seems to be associated with an increased expression level of the dopamine transporter and seems to mediate the MPH treatment response in ADHD patients.

Generalized pulp stones: report of a case with 6-year follow-up.

AIM: To present a mildly mentally retarded patient with generalized pulp stone formation and the six-year follow-up and to discuss the differential diagnosis of the case. SUMMARY: Pulp stones were radiographically detected in the pulp chamber of all permanent teeth in a 25-year-old woman with mild mental retardation who presented for endodontic treatment on tooth no 11 (FDI). The patient's medical, dental and family history was noncontributory. The pulp stone in the pulp chamber of tooth no 11 was removed during canal filing, and root canal treatment completed uneventfully. Six years later, the patient was re-evaluated and the pulp stones were unchanged radiographically. The patient's family history, facial phenotype and karyotype as well as the radiographic, laboratory and physical examination were not consistent with any of the known genetic syndromes associated with generalized pulp stones. Molecular analysis for the DSPP gene proved negative. The aetiology of this case remains unknown. KEY POINTS: Generalized pulp stones occur rarely; Such patients should be referred for genetic evaluation because pulp stones are mostly associated with genetic dentine defects; Pulp stones may hinder root canal treatment; Pulp stones may remain unchanged overtime.

Clinical variability of genetic isolates of Cohen syndrome.

Cohen syndrome (CS) (OMIM#216550) is an uncommon autosomal recessive developmental disorder that has been attributed to mutations in the COH1 gene in at least 200 patients of diverse ethnic background so far. The clinical heterogeneity of CS is evident when comparing patients of different ethnic backgrounds, especially when evaluating specific system phenotypes separately, such as the ophthalmic and central nervous systems. We reviewed the available clinical data on CS cohorts of patients who share a founder effect and demonstrated that most features associated so far with CS are less than those always present in the patients who share a founder mutation thus representing clinical heterogeneity. Furthermore, there is a wide clinical variability of CS in the distinct founder mutation cohorts, the Finnish, Greek/Mediterranean, Amish and Irish travelers. The Greek/Mediterranean founder mutation is correlated to a CS phenotype characterized by specific and persistent skeletal features, corneal changes, periodontal disease, a distinct neurocognitive phenotype for the high recurrence of autism and non-verbal communication and inconstant microcephaly.

LGI1 gene mutation screening in sporadic partial epilepsy with auditory features.

Partial epilepsy with auditory features occasionally segregates in families as an autosomal dominant trait. In some families mutations in the leucine-rich glioma inactivated (LGI1) gene have been identified. Sporadic cases might harbour either denovo or low-penetrant LGI1 mutations, which will substantially alter the family risk for epilepsy. We selected sixteen sporadic patients with cryptogenic temporal lobe epilepsy and partial seizures with auditory features. We compared clinical features of these patients with those of published autosomal dominant family cases. We screened these patients for LGI1 mutations. Comparing the sporadic patients with the published familial cases no difference in either the primary auditory features or in the other associated epileptic manifestations was identified. Sequence analysis of the whole LGI1 gene coding regions in sporadic patients did not reveal changes in the LGI1 gene. The genetic analysis demonstrates that LGI1 is not a major gene for sporadic cases of partial epilepsy with auditory features at least in the Italian population. Screening of sporadic patients for LGI1 mutations appears not useful in genetic counselling of these patients.

Preliminary data suggest that mutations in the CgRP pathway are not involved in human sporadic cryptorchidism.

In testicular descent to the scrotum, a multistep process, many anatomical and hormonal factors play a role. Cryptorchidism occurs in about 1-2% of males and may cause secondary degeneration of the testes. Animal models have shown that abnormalities, in the calcitonin gene-related peptide (CgRP) activity, could be relevant in the pathogenesis of cryptorchidism. We performed a mutation screening by PCR exon amplification, single-strand conformation polymorphism (SSCP) and sequencing in four candidate genes, CgRPs (alphaCgRP, betaCgRP), their receptor (CgRPR) and the receptor component protein (CgRP-RCP), in 90 selected cases of idiopathic unilateral or bilateral cryptorchidism. Mutation screening of the coding regions and intron-exon boundaries revealed some polymorphic variants but no pathogenic sequence changes. These preliminary data suggest that these genes are not major factors for cryptorchidism in humans.