The Invitae NSDHL-Related Disorders Panel analyzes the NSDHL gene, which is associated with congenital hemidysplasia with ichthyosiform nevus and limb defects (CHILD) syndrome and CK syndrome. CHILD syndrome affects females and presents with yellow, scaly skin and limb abnormalities at birth. CK syndrome affects males and is characterized by intellectual disability and behavioral problems and often presents with seizures and microcephaly in infancy.
Genetic testing of these genes may confirm a diagnosis and help guide treatment and management decisions. Identification of a disease-causing variant can inform recurrence-risk assessment and genetic counseling.
CHILD syndrome is a congenital disorder that affects females and is characterized by unilateral ichthyosiform skin lesions and ipsilateral limb hypoplasia ranging from shortening of the metacarpals and phalanges to absence of the entire limb. Other associated abnormalities include skeletal anomalies, central nervous system anomalies, heart defects, lung hypoplasia and renal anomalies. Intellect is usually normal. CHILD syndrome is usually male lethal during gestation.
CK syndrome affects males and is characterized by moderate-severe intellectual disability, behavioral problems, seizures, cerebral cortical malformations, microcephaly, distinctive facial features and a thin habitus.
NSDHL is the only gene known to be associated with CHILD and CK syndromes. Although CHILD syndrome is very rare, nearly all females with a clinical diagnosis of CHILD syndrome are found to have a pathogenic variant in NSDHL. The clinical sensitivity of identifying pathogenic variants in NSDHL in males with a clinical diagnosis of CK syndrome is unknown.
CHILD syndrome is X-linked dominant and typically lethal in males. CK syndrome is X-linked recessive and affects males, however, female heterozygous carriers may present with behavior problems.
CHILD syndrome is highly penetrant in females with clinical variability. CK syndrome is highly penetrant in males.
NSDHL-related disorders are rare and the prevalence is not clearly established.
The NSDHL-related disorder test could be considered in females with skin and limb abnormalities, and in males with central nervous system anomalies such as intellectual disability and behavioral abnormalities.
Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).
Our sequence analysis covers clinically important regions of each gene, including coding exons, +/- 10 base pairs of adjacent intronic sequence in the transcript listed below. In addition, analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any specific limitations in the analysis of these genes are also listed in the table below.
Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.
|Gene||Transcript reference||Sequencing analysis||Deletion/Duplication analysis|