Case: Fritzen Individual 2, male, German, AOR= 3 yo

CasePresentingHPOs: HP:0001511, HP:0001518, HP:0000252, HP:0000047, HP:0001643, HP:0001655, HP:0008947, HP:0001263, HP:0001344, HP:0001256, HP:0000486, HP:0000483, HP:000432, HP:0001357, HP:0000348, HP:0009890, HP:0000490, HP:0000455, HP:0000430, HP:0000343, HP:0010804, HP:0002714, HP:0012471, HP:0000047, HP:0001814, HP:0000752

CasePresentingText: intrauterine growth retardation noted at 22 weeks gestation. PFO/PDA closed spontaneously. Started walking at 18 months, at 3 years old no speech. EEG was not able to be evaluated.

CaseNOTHPOs: HP:0000365, HP:0001250

CasePreviousTesting: Chromosome analysis, microdeletion 22q11.2 testing, chromosomal microarray analysis, fragile X testing (FMR1) and methylation sensitive MLPA for chromosome 11 and 7 loci (Silver-Russell syndrome) testing were unremarkable and normal.

CaseGenotypingMethod: WES

Sanger sequencing was used to confirm the mutation and to exclude the presence of the mutant in the parents.

The WES identified a heterozygous mutation in ARID1A, a gene that is associated with Coffin-Siris syndrome. The mutation was a 6 bp duplication in (NM_006015.4:c.489_494dupCGCCGC, p.[(A164_A165dup)]. It was maternally inherited, and the mother was not noted to have behavioral abnormalities. In addition, the WES revealed 18 different mutations in 12 genes (Supplemental Table 1). Most of these were ruled out due to high frequencies in the control population in homozygoues state, or the genes were associated with disease entities that had disparate phenotypes than the those presenting in the proband.

Variant: chr2:g.48035302_48035303del; NM_001190274.1:c.2738_2739delAT (p.Y913X)

CA ID: CA658820925

de novo

gnomAD: not present

AddCaseInfo:

VariantEvidence: No variant evidence to confer alteration of FBXO11 function or pathogenicity. Furthermore, the presence of a VUS in ARID1A that is responsible for Coffin-Siris syndrome, which has many overlapping phenotype, cannot be ruled out as contributory, even in the absence of an strongly overt phenotype in the mother. Subtle behvioral phenotypes could be present, and she was not fully evaluated to rule out and behavioral abnormalities. Albeit, this mutation has arisen in another unrelated individual, de novo, in Martinez et al., 2017 (PMID: 27620904 ), as well as one patient, de novo in the DECIPHER DDD study (case 325596).Therefore, I am downgrading the score but minimally.

Case: Fritzen Individual 2, male, German, AOR= 3 yo

CasePresentingHPOs: HP:0001511, HP:0001518, HP:0000252, HP:0000047, HP:0001643, HP:0001655, HP:0008947, HP:0001263, HP:0001344, HP:0001256, HP:0000486, HP:0000483, HP:000432, HP:0001357, HP:0000348, HP:0009890, HP:0000490, HP:0000455, HP:0000430, HP:0000343, HP:0010804, HP:0002714, HP:0012471, HP:0000047, HP:0001814, HP:0000752

CasePresentingText: intrauterine growth retardation noted at 22 weeks gestation. PFO/PDA closed spontaneously. Started walking at 18 months, at 3 years old no speech. EEG was not able to be evaluated.

CaseNOTHPOs: HP:0000365, HP:0001250

CasePreviousTesting: Chromosome analysis, microdeletion 22q11.2 testing, chromosomal microarray analysis, fragile X testing (FMR1) and methylation sensitive MLPA for chromosome 11 and 7 loci (Silver-Russell syndrome) testing were unremarkable and normal.

CaseGenotypingMethod: WES

Sanger sequencing was used to confirm the mutation and to exclude the presence of the mutant in the parents.

The WES identified a heterozygous mutation in ARID1A, a gene that is associated with Coffin-Siris syndrome. The mutation was a 6 bp duplication in (NM_006015.4:c.489_494dupCGCCGC, p.[(A164_A165dup)]. It was maternally inherited, and the mother was not noted to have behavioral abnormalities. In addition, the WES revealed 18 different mutations in 12 genes (Supplemental Table 1). Most of these were ruled out due to high frequencies in the control population in homozygoues state, or the genes were associated with disease entities that had disparate phenotypes than the those presenting in the proband.

Variant: chr2:g.48035302_48035303del; NM_001190274.1:c.2738_2739delAT (p.Y913X)

CA ID: CA658820925

de novo

gnomAD: not present

AddCaseInfo:

VariantEvidence: No variant evidence to confer alteration of FBXO11 function or pathogenicity. Furthermore, the presence of a VUS in ARID1A that is responsible for Coffin-Siris syndrome, which has many overlapping phenotype, cannot be ruled out as contributory, even in the absence of an strongly overt phenotype in the mother. Subtle behvioral phenotypes could be present, and she was not fully evaluated to rule out and behavioral abnormalities. Albeit, this mutation has arisen in another unrelated individual, de novo, in Martinez et al., 2017 (PMID: 27620904 ), as well as one patient, de novo in the DECIPHER DDD study (case 325596).Therefore, I am downgrading the score but minimally.