CHAMP1-related disorders: pathomechanisms triggered by different genomic alterations define distinct nosological categories.

Loss-of-function variants in CHAMP1 were recently described as cause of a neurodevelopmental disorder characterized by intellectual disability (ID), autism, and distinctive facial characteristics. By exome sequencing (ES), we identified a truncating variant in CHAMP1, c.1858A > T (p.Lys620*), in a patient who exhibited a similar phenotype of severe ID and dysmorphisms. Whether haploinsufficiency or a dominant negative effect is the underlying pathomechanism in these cases is a question that still needs to be addressed. By array-CGH, we detected a 194 kb deletion in 13q34 encompassing CHAMP1, CDC16 and UPF3, in another patient who presented with borderline neurodevelopmental impairment and with no dysmorphisms. In a further patient suffering from early onset refractory seizures, we detected by ES a missense variant in CHAMP1, c.67 G > A (p.Gly23Ser). Genomic abnormalities were all de novo in our patients. We reviewed the clinical and the genetic data of patients reported in the literature with: loss-of-function variants in CHAMP1 (total 40); chromosome 13q34 deletions ranging from 1.1 to 4 Mb (total 7) and of the unique patient with a missense variant. We could infer that loss-of-function variants in CHAMP1 cause a homogeneous phenotype with severe ID, autism spectrum disorders (ASD) and highly distinctive facial characteristics through a dominant negative effect. CHAMP1 haploinsufficiency results in borderline ID with negligible consequences on the quality of life. Missense variants give rise to a severe epileptic encephalopathy through gain-of-function mechanism, most likely. We tentatively define for the first time distinct categories among the CHAMP1-related disorder on the basis of pathomechanisms.

Adult phenotype in Koolen-de Vries/KANSL1 haploinsufficiency syndrome.

BACKGROUND: Koolen-de Vries syndrome (KdVS) is a multisystem neurodevelopmental disorder caused by 17q21.31 deletions or mutations in KANSL1. It was mainly described in children. METHODS: A retrospective study on 9 subjects aged 19-45 years and revision of 18 literature patients, with the purpose to get insights into the phenotypic evolution with time, and into the clinical manifestations in adulthood. RESULTS: Seven patients had a 17q21.31 deletion and two a point mutation in KANSL1. All had intellectual disability, which was mild in five (56%) and moderate in four (44%). Epilepsy was diagnosed in four subjects (44%), with onset from 1 to 7 years and full remission before 9 years in 3/4 patients. Scoliosis affected seven individuals (77.7%) and it was substantially stable with age in 5/7 patients, allowing for simple daily activities. Two subjects had severely progressive scoliosis, which was surgically corrected. Overweight or true obesity did occur after puberty in six patients (67%). Behaviour abnormalities were recorded in six patients (67%). The facial phenotype slightly evolved with time to include thick eyebrows, elongated nose and pronounced pointed chin. Despite behaviour abnormalities, happy disposition and sociable attitudes were common. Half of patients had fluent language and were good at writing and reading. Rich language, although limited to single words or short sentences, and very limited or absent skills in writing and reading were observed in the remaining patients. Autonomy in daily activities and personal care was usually limited. CONCLUSIONS: Distinctive features in adult KdVS subjects include intellectual disability, overweight/obesity, behaviour abnormalities with preserved social interest, ability in language, slight worsening of the facial phenotype and no seizures.

Clinical Genetics Can Solve the Pitfalls of Genome-Wide Investigations: Lesson from Mismapping a Loss-of-Function Variant in KANSL1.

Massive parallel sequencing of 70 genes in a girl with a suspicion of chromatinopathy detected the (NM_015443.4:)c.985_986delTT variant in exon 2 of KANSL1, which led to a diagnostic consideration of Koolen De Vries syndrome. The same variant was present in the healthy mother, consistent with either incomplete penetrance or variant mismapping. A network of second opinion was implemented among clinical geneticists first, and a diagnosis of Koolen De Vries syndrome was considered unlikely. By MLPA, a duplication spanning exons 1-3 of KANSL1 was detected in both the mother and the daughter. On cDNA sequencing, biallelic wild type mRNA was observed. We concluded that the variant affects the noncoding duplicated gene region in our family, and we finally classified it as benign. Parallel wide genomic sequencing is increasingly the first genetic investigation in individuals with intellectual disability. The c.985_986delTT variant in KANSL1 was described both in individuals with typical KdVS and in a limited number of healthy subjects. This report highlights the role of clinical genetics to correctly classify variants and to define proper clinical and diagnostic correlations.

A novel truncating variant within exon 7 of KAT6B associated with features of both Say-Barber-Bieseker-Young-Simpson syndrome and genitopatellar syndrome: Further evidence of a continuum in the clinical spectrum of KAT6B-related disorders.

KAT6B sequence variants have been identified in both patients with the Say-Barber-Biesecker-Young-Simpson syndrome (SBBYSS) and in the genitopatellar syndrome (GPS). In SBBYSS, they were reported to affect mostly exons 16-18 of KAT6B, and the predicted mechanism of pathogenesis was haploinsufficiency or a partial loss of protein function. Truncating variants in KAT6B leading to GPS appear to cluster within the proximal portion of exon 18, associated with a dominant-negative effect of the mutated protein, most likely. Although SBBYSS and GPS have been initially considered allelic disorders with distinctive genetic and clinical features, there is evidence that they represent two ends of a spectrum of conditions referable as KAT6B-related disorders. We detected a de novo truncating variant within exon 7 of KAT6B in a 8-year-old female who presented with mild intellectual disability, facial dysmorphisms highly consistent with SBBYSS, and skeletal anomalies including exostosis, that are usually considered component manifestations of GPS. Following the clinical diagnosis driven by the striking facial phenotype, we analyzed the KAT6B gene by NGS techniques. The present report highlights the pivotal role of clinical genetics in avoiding clear-cut genotype-phenotype categories in syndromic forms of intellectual disability. In addition, it further supports the evidence that a continuum exists within the clinical spectrum of KAT6B-associated disorders.

Syndromic Craniosynostosis Can Define New Candidate Genes for Suture Development or Result from the Non-specifc Effects of Pleiotropic Genes: Rasopathies and Chromatinopathies as Examples.

Craniosynostosis is a heterogeneous condition caused by the premature fusion of cranial sutures, occurring mostly as an isolated anomaly. Pathogenesis of non-syndromic forms of craniosynostosis is largely unknown. In about 15-30% of cases craniosynostosis occurs in association with other physical anomalies and it is referred to as syndromic craniosynostosis. Syndromic forms of craniosynostosis arise from mutations in genes belonging to the Fibroblast Growth Factor Receptor (FGFR) family and the interconnected molecular pathways in most cases. However it can occur in association with other gene variants and with a variety of chromosome abnormalities as well, usually in association with intellectual disability (ID) and additional physical anomalies. Evaluating the molecular properties of the genes undergoing intragenic mutations or copy number variations (CNVs) along with prevalence of craniosynostosis in different conditions and animal models if available, we made an attempt to define two distinct groups of unusual syndromic craniosynostosis, which can reflect direct effects of emerging new candidate genes with roles in suture homeostasis or a non-specific phenotypic manifestation of pleiotropic genes, respectively. RASopathies and 9p23p22.3 deletions are reviewed as examples of conditions in the first group. In particular, we found that craniosynostosis is a relatively common component manifestation of cardio-facio-cutaneous (CFC) syndrome. Chromatinopathies and neurocristopathies are presented as examples of conditions in the second group. We observed that craniosynostosis is uncommon on average in these conditions. It was randomly associated with Kabuki, Koolen-de Vries/KANSL1 haploinsufficiency and Mowat-Wilson syndromes and in KAT6B-related disorders. As an exception, trigonocephaly in Bohring-Opitz syndrome reflects specific molecular properties of the chromatin modifier ASXL1 gene. Surveillance for craniosynostosis in syndromic forms of intellectual disability, as well as ascertainment of genomic CNVs by array-CGH in apparently non-syndromic craniosynostosis is recommended, to allow for improvement of both the clinical outcome of patients and the accurate individual diagnosis.

Impairment of different protein domains causes variable clinical presentation within Pitt-Hopkins syndrome and suggests intragenic molecular syndromology of TCF4.

Pitt-Hopkins syndrome is a neurodevelopmental disorder characterized by severe intellectual disability and a distinctive facial gestalt. It is caused by haploinsufficiency of the TCF4 gene. The TCF4 protein has different functional domains, with the NLS (nuclear localization signal) domain coded by exons 7-8 and the bHLH (basic Helix-Loop-Helix) domain coded by exon 18. Several alternatively spliced TCF4 variants have been described, allowing for translation of variable protein isoforms. Typical PTHS patients have impairment of at least the bHLH domain. To which extent impairment of the remaining domains contributes to the final phenotype is not clear. There is recent evidence that certain loss-of-function variants disrupting TCF4 are associated with mild ID, but not with typical PTHS. We describe a frameshift-causing partial gene deletion encompassing exons 4-6 of TCF4 in an adult patient with mild ID and nonspecific facial dysmorphisms but without the typical features of PTHS, and a c.520C > T nonsense variant within exon 8 in a child presenting with a severe phenotype largely mimicking PTHS, but lacking the typical facial dysmorphism. Investigation on mRNA, along with literature review, led us to suggest a preliminary phenotypic map of loss-of-function variants affecting TCF4. An intragenic phenotypic map of loss-of-function variants in TCF4 is suggested here for the first time: variants within exons 1-4 and exons 4-6 give rise to a recurrent phenotype with mild ID not in the spectrum of Pitt-Hopkins syndrome (biallelic preservation of both the NLS and bHLH domains); variants within exons 7-8 cause a severe phenotype resembling PTHS but in absence of the typical facial dysmorphism (impairment limited to the NLS domain); variants within exons 9-19 cause typical Pitt-Hopkins syndrome (impairment of at least the bHLH domain). Understanding the TCF4 molecular syndromology can allow for proper nosology in the current era of whole genomic investigations.