Correction: KAT6A Syndrome: genotype-phenotype correlation in 76 patients with pathogenic KAT6A variants.

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KAT6A Syndrome: genotype-phenotype correlation in 76 patients with pathogenic KAT6A variants.

PURPOSE: Pathogenic variants in KAT6A have recently been identified as a cause of syndromic developmental delay. Within 2 years, the number of patients identified with pathogenic KAT6A variants has rapidly expanded and the full extent and variability of the clinical phenotype has not been reported. METHODS: We obtained data for patients with KAT6A pathogenic variants through three sources: treating clinicians, an online family survey distributed through social media, and a literature review. RESULTS: We identified 52 unreported cases, bringing the total number of published cases to 76. Our results expand the genotypic spectrum of pathogenic variants to include missense and splicing mutations. We functionally validated a pathogenic splice-site variant and identified a likely hotspot location for de novo missense variants. The majority of clinical features in KAT6A syndrome have highly variable penetrance. For core features such as intellectual disability, speech delay, microcephaly, cardiac anomalies, and gastrointestinal complications, genotype- phenotype correlations show that late-truncating pathogenic variants (exons 16-17) are significantly more prevalent. We highlight novel associations, including an increased risk of gastrointestinal obstruction. CONCLUSION: Our data expand the genotypic and phenotypic spectrum for individuals with genetic pathogenic variants in KAT6A and we outline appropriate clinical management.

Clinical and molecular characteristics in three families with biallelic mutations in IGHMBP2.

Biallelic mutations in IGHMBP2 cause spinal muscular atrophy with respiratory distress type 1 (SMARD1) or Charcot-Marie-Tooth type 2S (CMT2S). We report three families variably affected by IGHMBP2 mutations. Patient 1, an 8-year-old boy with two homozygous variants: c.2T>C and c.861C>G, was wheelchair bound due to sensorimotor axonal neuropathy and chronic respiratory failure. Patient 2 and his younger sister, Patient 3, had compound heterozygous variants: c.983_987delAAGAA and c.1478C>T. However, clinical phenotypes differed markedly as the elder with sensorimotor axonal neuropathy had still unaffected respiratory function at 4.5 years, whereas the younger presented as infantile spinal muscular atrophy and died from relentless respiratory failure at 11 months. Patient 4, a 6-year-old girl homozygous for IGHMBP2 c.449+1G>T documented to result in two aberrant transcripts, was wheelchair dependent due to axonal polyneuropathy. The clinical presentation in Patients 1 and 3 were consistent with SMARD1, whereas Patients 2 and 4 were in agreement with CMT2S.

Kaufman oculocerebrofacial syndrome in sisters with novel compound heterozygous mutation in UBE3B.

A pair of sisters was ascertained for multiple congenital defects, including marked craniofacial dysmorphisms with blepharophimosis, and severe psychomotor delay. Two novel compound heterozygous mutations in UBE3B were identified in both the sisters by exome sequencing. These mutations include c.1A>G, which predicts p.Met1?, and a c.1773delC variant, predicted to cause a frameshift at p.Phe591fs. UBE3B encodes a widely expressed protein ubiquitin ligase E3B, which, when mutated in both alleles, causes Kaufman oculocerebrofacial syndrome. We report on the thorough clinical examination of the patients and review the state of art knowledge of this disorder.

Haploinsufficiency of two histone modifier genes on 6p22.3, ATXN1 and JARID2, is associated with intellectual disability.

BACKGROUND: Nineteen patients with deletions in chromosome 6p22-p24 have been published so far. The syndromic phenotype is varied, and includes intellectual disability, behavioural abnormalities, dysmorphic features and structural organ defects. Heterogeneous deletion breakpoints and sizes (1-17 Mb) and overlapping phenotypes have made the identification of the disease causing genes challenging. We suggest JARID2 and ATXN1, both harbored in 6p22.3, as disease causing genes. METHODS AND RESULTS: We describe five unrelated patients with de novo deletions (0.1-4.8 Mb in size) in chromosome 6p22.3-p24.1 detected by aCGH in a cohort of approximately 3600 patients ascertained for neurodevelopmental disorders. Two patients (Patients 4 and 5) carried non-overlapping deletions that were encompassed by the deletions of the remaining three patients (Patients 1-3), indicating the existence of two distinct dosage sensitive genes responsible for impaired cognitive function in 6p22.3 deletion-patients. The smallest region of overlap (SRO I) in Patients 1-4 (189 kb) included the genes JARID2 and DTNBP1, while SRO II in Patients 1-3 and 5 (116 kb) contained GMPR and ATXN1. Patients with deletion of SRO I manifested variable degrees of cognitive impairment, gait disturbance and distinct, similar facial dysmorphic features (prominent supraorbital ridges, deep set eyes, dark infraorbital circles and midface hypoplasia) that might be ascribed to the haploinsufficiency of JARID2. Patients with deletion of SRO II showed intellectual disability and behavioural abnormalities, likely to be caused by the deletion of ATXN1. Patients 1-3 presented with lower cognitive function than Patients 4 and 5, possibly due to the concomitant haploinsufficiency of both ATXN1 and JARID2. The chromatin modifier genes ATXN1 and JARID2 are likely candidates contributing to the clinical phenotype in 6p22-p24 deletion-patients. Both genes exert their effect on the Notch signalling pathway, which plays an important role in several developmental processes. CONCLUSIONS: Patients carrying JARID2 deletion manifested with cognitive impairment, gait disturbance and a characteristic facial appearance, whereas patients with deletion of ATXN1 seemed to be characterized by intellectual disability and behavioural abnormalities. Due to the characteristic facial appearance, JARID2 haploinsufficiency might represent a clinically recognizable neurodevelopmental syndrome.

Mutation screening of PTPN22: association of the 1858T-allele with Addison's disease.

The tyrosine-protein phosphatase non-receptor type 22 (PTPN22) gene was recently identified as an important genetic susceptibility factor in several autoimmune diseases. The increased risk has been broadly explained by the 1858T-allele (rs2476601). As two smaller studies on Addison's disease (AD) have shown diverging results, we aimed to elucidate the predisposing effect of the single-nucleotide polymorphism (SNP) 1858CT in a larger population of AD patients, especially focusing on the AD patients with known autoimmune etiology. We also screened for unknown rare or common variants in the PTPN22 gene that could predispose for AD. The case-control study of Norwegian AD patients (n=332) and controls (n=990) showed a significant association between autoimmune AD (n=302) and the PTPN22 1858T risk allele (P=0.016). The association of AD with 1858T was supported by a meta-analysis combining our genotype data with that of others published previously (P=0.003). The mutation screening of PTPN22 in AD patients (n=332) and controls (n=112) revealed eight missense variants, five of which have not been reported previously. In conclusion, the 1858T-allele is a PTPN22 genetic susceptibility factor for autoimmune AD. Other rare variants in PTPN22 do occur, and may also be involved in the pathogenesis.

CTLA4 polymorphisms are associated with vitiligo, in patients with concomitant autoimmune diseases.

The cytotoxic T lymphocyte antigen4 (CTLA4) gene plays a critical role in the control of T cell activation. The gene encodes a surface molecule with inhibitory effects on activated T cells. Several studies have disclosed an association between the previously known variants of the CTLA4 gene and autoimmune disorders, but no study has as yet found any definite association between vitiligo and the CTLA4 polymorphisms. A recent study identified new candidate susceptibility polymorphisms in this region, associated with differential gene splicing and thereby the relative abundance of soluble CTLA4. To assess these new polymorphisms in patients with vitiligo, we genotyped 100 vitiligo patients and 140 healthy controls from the UK, for these novel polymorphisms. No association was found in patients with isolated vitiligo, but a significant association was seen in patients with vitiligo and other autoimmune diseases. The results indicate that the polymorphisms in the CTLA4 gene region confer susceptibility to vitiligo when occurring together with other autoimmune diseases, but not in patients with isolated vitiligo. This raises the possibility that there are two distinct forms of vitiligo where only a subgroup of patients may have a disease caused by the autoimmune destruction of melanocytes.

Polymorphisms in the cytotoxic T lymphocyte antigen-4 gene region confer susceptibility to Addison's disease.

The cytotoxic T lymphocyte antigen-4 (CTLA4) gene on chromosome 2q33 encodes a key regulator in the adaptive immune system. The CTLA4 surface molecule is expressed on activated T lymphocytes and involved in down-regulation of the immune response. Previous studies on a possible association between autoimmune Addison's disease and CTLA4 polymorphisms have shown conflicting results. A recent study identified new candidate polymorphisms in the CTLA4 region, influencing gene splicing and thereby the relative abundance of soluble CTLA4. We genotyped 134 patients with Addison's disease and 413 healthy controls from Norway and United Kingdom for these newly identified polymorphisms. Our data demonstrate that the same polymorphisms that have recently been demonstrated to confer susceptibility to autoimmune thyroid disease and type 1 diabetes also confer susceptibility to Addison's disease. This finding suggests that polymorphisms in CTLA4 confer general risk to develop autoimmunity and identifies a potential therapeutic target in the prevention of autoimmune endocrine disorders.