Mendelian neurodevelopmental disorders customarily present with complex and overlapping symptoms, complicating the clinical diagnosis. Individuals with a growing number of the so-called rare ...disorders exhibit unique, disorder-specific DNA methylation patterns, consequent to the underlying gene defects. Besides providing insights to the pathophysiology and molecular biology of these disorders, we can use these epigenetic patterns as functional biomarkers for the screening and diagnosis of these conditions. This review summarizes our current understanding of DNA methylation episignatures in rare disorders and describes the underlying technology and analytical approaches. We discuss the computational parameters, including statistical and machine learning methods, used for the screening and classification of genetic variants of uncertain clinical significance. Describing the rationale and principles applied to the specific computational models that are used to develop and adapt the DNA methylation episignatures for the diagnosis of rare disorders, we highlight the opportunities and challenges in this emerging branch of diagnostic medicine.
A growing number of genetic neurodevelopmental disorders are known to be associated with unique genomic DNA methylation patterns, called episignatures, which are detectable in peripheral blood. The ...intellectual developmental disorder, X-linked, syndromic, Armfield type (MRXSA) is caused by missense variants in
. Functional studies revealed the pathogenesis to be a spliceosomopathy that is characterized by atypical mRNA processing during development. In this study, we assessed the peripheral blood specimens in a cohort of individuals with MRXSA and detected a unique and highly specific DNA methylation episignature associated with this disorder. We used this episignature to construct a support vector machine model capable of sensitive and specific identification of individuals with pathogenic variants in
. This study contributes to the expanding number of genetic neurodevelopmental disorders with defined DNA methylation episignatures, provides an additional understanding of the associated molecular mechanisms, and further enhances our ability to diagnose patients with rare disorders.
The 22q11.2 deletion syndrome (22q11.2DS) is the most common genomic disorder in humans and is the result of a recurrent 1.5 to 2.5 Mb deletion, encompassing approximately 20–40 genes, respectively. ...The clinical presentation of the typical deletion includes: Velocardiofacial, Di George, Opitz G/BBB and Conotruncalanomaly face syndromes. Atypical deletions (proximal, distal or nested) are rare and characterized mainly by normal phenotype or mild intellectual disability and variable clinical features. The pathogenetic mechanisms underlying this disorder are not completely understood. Because the 22q11.2 region harbours genes coding for transcriptional factors and chromatin remodelers, in this study, we performed analysis of genome-wide DNA methylation of peripheral blood from 49 patients with 22q11.2DS using the Illumina Infinium Methylation EPIC bead chip arrays. This cohort comprises 43 typical, 2 proximal and 4 distal deletions. We demonstrated the evidence of a unique and highly specific episignature in all typical and proximal 22q11.2DS. The sensitivity and specificity of this signature was further confirmed by comparing it to over 1500 patients with other neurodevelopmental disorders with known episignatures. Mapping the 22q11.2DS DNA methylation episignature provides both novel insights into the molecular pathogenesis of this disorder and an effective tool in the molecular diagnosis of 22q11.2DS.
JARID2 (Jumonji, AT Rich Interactive Domain 2) pathogenic variants cause a neurodevelopmental syndrome, that is characterized by developmental delay, cognitive impairment, hypotonia, autistic ...features, behavior abnormalities and dysmorphic facial features. JARID2 encodes a transcriptional repressor protein that regulates the activity of various histone methyltransferase complexes. However, the molecular etiology is not fully understood, and JARID2-neurodevelopmental syndrome may vary in its typical clinical phenotype. In addition, the detection of variants of uncertain significance (VUSs) often results in a delay of final diagnosis which could hamper the appropriate care. In this study we aim to detect a specific and sensitive DNA methylation signature for JARID2-neurodevelopmental syndrome. Peripheral blood DNA methylation profiles from 56 control subjects, 8 patients with (likely) pathogenic JARID2 variants and 3 patients with JARID2 VUSs were analyzed. DNA methylation analysis indicated a clear and robust separation between patients with (likely) pathogenic variants and controls. A binary model capable of classifying patients with the JARID2-neurodevelopmental syndrome was constructed on the basis of the identified episignature. Patients carrying VUSs clustered with the control group. We identified a distinct DNA methylation signature associated with JARID2-neurodevelopmental syndrome, establishing its utility as a biomarker for this syndrome and expanding the EpiSign diagnostic test.
JARID2 (Jumonji, AT-rich interactive domain 2) haploinsufficiency is associated with a clinically distinct neurodevelopmental syndrome. It is characterized by intellectual disability, developmental ...delay, autistic features, behavior abnormalities, cognitive impairment, hypotonia, and dysmorphic features. JARID2 acts as a transcriptional repressor protein that is involved in the regulation of histone methyltransferase complexes. JARID2 plays a role in the epigenetic machinery, and the associated syndrome has an identified DNA methylation episignature derived from sequence variants and intragenic deletions involving JARID2. For this study, our aim was to determine whether patients with larger deletions spanning beyond JARID2 present a similar DNA methylation episignature and to define the critical region involved in aberrant DNA methylation in 6p22–p24 microdeletions. We examined the DNA methylation profiles of peripheral blood from 56 control subjects, 13 patients with (likely) pathogenic JARID2 variants or patients carrying copy number variants, and three patients with JARID2 VUS variants. The analysis showed a distinct and strong differentiation between patients with (likely) pathogenic variants, both sequence and copy number, and controls. Using the identified episignature, we developed a binary model to classify patients with the JARID2-neurodevelopmental syndrome. DNA methylation analysis indicated that JARID2 is the driver gene for aberrant DNA methylation observed in 6p22–p24 microdeletions. In addition, we performed analysis of functional correlation of the JARID2 genome-wide methylation profile with the DNA methylation profiles of 56 additional neurodevelopmental disorders. To conclude, we refined the critical region for the presence of the JARID2 episignature in 6p22–p24 microdeletions and provide insight into the functional changes in the epigenome observed when regulation by JARID2 is lost.
Wiedemann-Steiner syndrome (WDSTS) is a Mendelian syndromic intellectual disability (ID) condition associated with hypertrichosis cubiti, short stature, and characteristic facies caused by pathogenic ...variants in the
gene. Clinical features can be inconclusive in mild and unusual WDSTS presentations with variable ID (mild to severe), facies (typical or not) and other associated malformations (bone, cerebral, renal, cardiac and ophthalmological anomalies). Interpretation and classification of rare
variants can be challenging. A genome-wide DNA methylation episignature for
-related syndrome could allow functional classification of variants and provide insights into the pathophysiology of WDSTS. Therefore, we assessed genome-wide DNA methylation profiles in a cohort of 60 patients with clinical diagnosis for WDSTS or Kabuki and identified a unique highly sensitive and specific DNA methylation episignature as a molecular biomarker of WDSTS. WDSTS episignature enabled classification of variants of uncertain significance in the
gene as well as confirmation of diagnosis in patients with clinical presentation of WDSTS without known genetic variants. The changes in the methylation profile resulting from
mutations involve global reduction in methylation in various genes, including homeobox gene promoters. These findings provide novel insights into the molecular etiology of WDSTS and explain the broad phenotypic spectrum of the disease.
In 1978, Huang and Rosa solved the spectrum problem for decomposition for trees with up to eight edges. Also, the packing and covering problems were settled for trees with up to six edges by Roditty. ...In this paper, we find the spectrum of excess graphs for trees with up to four edges. Moreover, we use new techniques in our proofs and state lemmas that will be useful for generalizing our result for trees with higher number of edges.
Let X,Y be finite sets, r,s,h,λ∈N with s≥r,X⊊Y. By λXh we mean the collection of all h-subsets of X where each subset occurs λ times. A coloring (partition) of λXh is r-regular if each element of X ...is in exactly r subsets of each color. A one-regular color class is a perfect matching. We are interested in necessary and sufficient conditions under which an r-regular coloring of λXh can be embedded into an s-regular coloring of λYh. Using algebraic techniques involving glueing together orbits of a suitably chosen cyclic group, the first author and Newman solved the case when λ=1,r=s,gcd(|X|,|Y|,h)=gcd(|Y|,h). Using purely combinatorial techniques, we nearly settle the case h=4.
It is worth noting that completing partial symmetric latin squares is closely related to the case λ=r=s=1,h=2 which was solved by Cruse.
A coloring (partition) of the collection
(
X
h
) of all
h‐subsets of a set
X is
r‐regular if the number of times each element of
X appears in each color class (all sets of the same color) is the same ...number
r. We are interested in finding the conditions under which a given
r‐regular coloring of
(
X
h
) is extendible to an
s‐regular coloring of
(
Y
h
) for
s
⩾
r and
Y
⊋
X. The case
h
=
2
,
r
=
s
=
1 was solved by Cruse, and due to its connection to completing partial symmetric latin squares, many related problems are extensively studied in the literature, but very little is known for
h
⩾
3. The case
r
=
s
=
1 was solved by Häggkvist and Hellgren, settling a conjecture of Brouwer and Baranyai. The cases
h
=
2 and
h
=
3 were solved by Rodger and Wantland, and Bahmanian and Newman, respectively. In this paper, we completely settle the cases
h
=
4
,
|
Y
|
⩾
4
|
X
| and
h
=
5
,
|
Y
|
⩾
5
|
X
|.
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