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Alternative genomic diagnoses for individuals with a clinical diagnosis of Dubowitz syndrome.

ABSTRACT: Dubowitz syndrome (DubS) is considered a recognizable syndrome characterized by a distinctive facial appearance and deficits in growth and development. There have been over 200 individuals reported with Dubowitz or a "Dubowitz-like" condition, although no single gene has been implicated as responsible for its cause. We have performed exome (ES) or genome sequencing (GS) for 31 individuals clinically diagnosed with DubS. After genome-wide sequencing, rare variant filtering and computational and Mendelian genomic analyses, a presumptive molecular diagnosis was made in 13/27 (48%) families. The molecular diagnoses included biallelic variants in SKIV2L, SLC35C1, BRCA1, NSUN2; de novo variants in ARID1B, ARID1A, CREBBP, POGZ, TAF1, HDAC8, and copy-number variation at1p36.11(ARID1A), 8q22.2(VPS13B), Xp22, and Xq13(HDAC8). Variants of unknown significance in known disease genes, and also in genes of uncertain significance, were observed in 7/27 (26%) additional families. Only one gene, HDAC8, could explain the phenotype in more than one family (N = 2). All but two of the genomic diagnoses were for genes discovered, or for conditions recognized, since the introduction of next-generation sequencing. Overall, the DubS-like clinical phenotype is associated with extensive locus heterogeneity and the molecular diagnoses made are for emerging clinical conditions sharing characteristic features that overlap the DubS phenotype.

SUBMITTER: Dyment DA

PROVIDER: S-EPMC8197629 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Dubowitz syndrome is a rare disorder characterized by multiple congenital anomalies, cognitive delay, growth failure, an immune defect, and an increased risk of blood dyscrasia and malignancy. There is considerable phenotypic variability, suggesting genetic heterogeneity. We clinically characterized and performed exome sequencing and high-density array SNP genotyping on three individuals with Dubowitz syndrome, including a pair of previously-described siblings (Patients 1 and 2, brother and sister) and an unpublished patient (Patient 3). Given the siblings' history of bone marrow abnormalities, we also evaluated telomere length and performed radiosensitivity assays. In the siblings, exome sequencing identified compound heterozygosity for a known rare nonsense substitution in the nuclear ligase gene LIG4 (rs104894419, NM_002312.3:c.2440C>T) that predicts p.Arg814X (MAF:0.0002) and an NM_002312.3:c.613delT variant that predicts a p.Ser205Leufs*29 frameshift. The frameshift mutation has not been reported in 1000 Genomes, ESP, or ClinSeq. These LIG4 mutations were previously reported in the sibling sister; her brother had not been previously tested. Western blotting showed an absence of a ligase IV band in both siblings. In the third patient, array SNP genotyping revealed a de novo ? 3.89 Mb interstitial deletion at chromosome 17q24.2 (chr 17:62,068,463-65,963,102, hg18), which spanned the known Carney complex gene PRKAR1A. In all three patients, a median lymphocyte telomere length of ? 1st centile was observed and radiosensitivity assays showed increased sensitivity to ionizing radiation. Our work suggests that, in addition to dyskeratosis congenita, LIG4 and 17q24.2 syndromes also feature shortened telomeres; to confirm this, telomere length testing should be considered in both disorders. Taken together, our work and other reports on Dubowitz syndrome, as currently recognized, suggest that it is not a unitary entity but instead a collection of phenotypically similar disorders. As a clinical entity, Dubowitz syndrome will need continual re-evaluation and re-definition as its constituent phenotypes are determined.

Project description:BackgroundAutism is a developmental condition, where symptoms are expected to occur in childhood, but a significant number of individuals are diagnosed with autism for the first time in adulthood. Here, we examine diagnoses given in childhood among individuals that are diagnosed with autism in adulthood, to investigate whether the late autism diagnosis might be explained by misdiagnosis in childhood or diagnostic overshadowing.MethodsThrough the Danish National Patient Registry, we identified individuals diagnosed with autism in adulthood (N = 2199), as well as a control sample with no records of an autism diagnosis (N = 460,798) and calculated how many had received different psychiatric or neurological diagnoses in childhood.ResultsWe found that most childhood diagnoses were overrepresented in those with an adult autism diagnosis, and attention-deficit hyperactivity disorder, affective disorders, anxiety, and stress disorders were the most prevalent childhood conditions in this group. However, 69% of males and 61% of females with adult autism diagnoses were not found to have received any of the investigated diagnoses before 18 years of age, and most childhood diagnoses were given after the age of 12.LimitationsMilder to moderate cases of psychiatric conditions that have been solely treated by family physicians or school psychologists may not be fully included in our dataset. The study is based on data from the Danish health care system, and further research is needed to assess whether the findings can be generalized to other countries.ConclusionA majority of those with an adult autism diagnosis had no records of having received any of the investigated diagnoses in childhood. In these cases, the late autism diagnosis is therefore unlikely to be explained by either misdiagnosis or overshadowing. This result is at odds with the prevailing notion that autistic symptoms tend to diminish with age. Therefore, further research is warranted to examine how and if early signs of autism may have manifested among these individuals, and how similar they are to autistic people diagnosed earlier in their development.

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Alternative genomic diagnoses for individuals with a clinical diagnosis of Dubowitz syndrome.

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