Monthly Archives: January 2019

Decoding Neurogenetic Answers- Case Study #2

Patient Clinical Information: The proband is a 6-year-old female with developmental delays including speech and motor delays, subtle dysmorphic features including close set eyes, low set ears and wide space between toes, decreased IQ and staring episodes concerning for seizures.

Family History: There is no reported family history for this case.

Testing Ordered: MNG Exome™ Trio Sequencing + mtDNA

Genetic Findings: No variants that would explain the patient’s phenotype were identified through exome or mitochondrial DNA sequencing. Through copy number analysis, a heterozygous deletion of chromosome 16p11.2 was found.

Outcome: The diagnosis for this patient is 16p11.2 deletion syndrome, which is autosomal dominant. The deletion is 618 kilobases in size, encompasses 34 genes, and is consistent with other pathogenic, similarly sized deletions in this region. This variant was not detected in the patient’s parents, indicating that it is de novo.

This disorder is characterized by developmental delay, intellectual disability and speech delay. Some individuals with 16p11.2 deletion syndrome are also reported to have minor dysmorphic features, including low set ears and partial syndactyly of toes, which is consistent with the clinical history provided for this patient. Additionally, recurrent seizures have been reported, which may explain the staring episodes include in the proband’s clinical history. In this case, copy number analysis was key in determining the cause of the patient’s phenotype. Had the clinician ordered an exome without copy number analysis, they would have received a negative report.

Figure1: This image is from our copy number output via the Dragen pipeline. Each red and green colored bar represents approximately 250 base pairs of sequence. The blue band shown under the proband track indicates an area consistent with heterozygous deletion, as indicated by the red bars directly above it. Directly under the solid blue bar is the zygosity track, showing apparent homozygosity for all calls in this region. This 16p11.2 deletion is clearly present in the proband, and absent in both the mother and father’s copy number data.

Reported by: Rebecca Kelly, MB(ASCP)CM

Decoding Neurogenetic Answers- Case Study #1

Patient Clinical Information: The proband is an 18-month-old female presenting with developmental delays and multiple dysmorphic features. Previous testing identified two known pathogenic variants linked to acyl CoA dehydrogenase deficiency.

Family History: The proband’s mother reports a history of hypoglycemia and epilepsy since childhood, both of which are not currently seen in the proband.

Testing Ordered: MNG Exome™ Trio Sequencing + mtDNA

Genetic Findings: Exome sequencing detected a heterozygous duplication of four nucleotides in the gene SETD2. The variant was detected in 42% of the reads in the proband, which is consistent with heterozygosity. However, the variant was only detected in 14% of reads for the patient’s mother, consistent with her being mosaic for this variant.

The SETD2 gene acts in an autosomal dominant manner. This particular variant is expected to result in premature truncation of the protein, which is a known mechanism of disease for SETD2.

Several other variants were also detected, both pathogenic and VUS, which may be consistent with additional clinical presentations identified in this patient.

Outcome: The diagnosis for this patient is consistent with Luscan-Lumish syndrome. This disorder is characterized by a variety of features, including dysmorphic features and developmental delay, which is consistent with the clinical history provided for the patient. Individuals with this syndrome may also present with seizures. Since the patient’s mother is mosaic for this variant, this may explain her history of epilepsy. It is important to note that while the proband is not reported to have seizures at this time, they may be at risk for developing seizures during their childhood. In this case, the presence of mosaicism in a known pathogenic variant explains two seemingly different phenotypes in a patient and her mother.

 

Figure 1: A heterozygous SETD2 c.779_783dup p.Ser262Leufs*4 variant (72/173 reads, 42%) was detected in the proband. The same variant was also detected at low levels (20/140 reads, 14%) in the patient’s mother, and not found in the father.

Reported by: Rebecca Kelly, MB(ASCP)CM