Microphthalmia with Linear Skin Defects: HCCS Gene Deletion/Duplication

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Condition Description

Microphthalmia with linear skin defects (MLS) syndrome (OMIM #309801) is characterized by unilateral or bilateral microphthalmia and/or anophthalmia and linear skin defects (areas of aplastic skin) ,which are usually present at birth and involve the face and neck.  Overtime these lesions heal and leave minimal residual scarring.  Minor criteria of MLS syndrome include other ocular abnormalities such as microcornea and, central nervous system involvement including agenesis of the corpus callosum and microcephaly, intellectual disability, infantile seizures, and congenital heart defects.  Short stature, diaphragmatic hernia, nail dystrophy, hearing loss, and genitourinary malformations may also be present. 

MLS syndrome is inherited in an X-linked manner and is usually lethal in males.  Most cases present as a single occurrence in a family, however, familial occurrences have been described.  Both intra- and interfamilial variability is possible.

Diagnosis is based on clinical findings and the detection of either a chromosomal abnormality that results in monosomy for Xp22 or a mutation in the HCCS gene (Xp22) (OMIM #300056), the only gene known to be associated with MLS syndrome.  Approximately 77% of affected individuals have monosomy Xp22 due to either a chromosomal abnormality or an interstitial deletion.  Both point mutations and multiple exon deletions of the HCCS gene have been reported. 

For patients with suspected MLS syndrome, sequence analysis is recommended as the first step in mutation identification. For patients in whom mutations are not identified by full gene sequencing, deletion/duplication analysis is appropriate.

References:

Genes (1)

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Indications

This test is indicated for:
  • Confirmation of a clinical diagnosis of MLS syndrome in an individual in whom sequence analysis was negative.
  • Carrier testing in adults with a family history of MLS syndrome in whom sequence analysis was negative.

Methodology

DNA isolated from peripheral blood is hybridized to a CGH array to detect deletions and duplications. The targeted CGH array has overlapping probes which cover the entire genomic region.


Please note that a "backbone" of probes across the entire genome are included on the array for analytical and quality control purposes. Rarely, off-target copy number variants causative of disease may be identified that may or may not be related to the patient's phenotype. Only known pathogenic off-target copy number variants will be reported. Off-target copy number variants of unknown clinical significance will not be reported.

Detection

Detection is limited to duplications and deletions. The CGH array will not detect point or intronic mutations. Results of molecular analysis must be interpreted in the context of the patient's clinical and/or biochemical phenotype.

Specimen Requirements

Submit only 1 of the following specimen types

Preferred specimen type: Whole Blood

Type: Whole Blood

Specimen Requirements:

In EDTA (purple top) or ACD (yellow top) tube:
Infants (<2 years): 2-3 ml
Children (>2 years): 3-5 ml
Older Children & Adults: 5-10 ml

Specimen Collection and Shipping: Refrigerate until time of shipment. Ship sample within 5 days of collection at room temperature with overnight delivery.

Type: Saliva

Specimen Requirements:

OrageneTM Saliva Collection kit (available through EGL) used according to manufacturer instructions.

Specimen Collection and Shipping: Store sample at room temperature. Ship sample within 5 days of collection at room temperature with overnight delivery.

  • Sequence analysis of the HCCS gene is available and is required before deletion/duplication analysis.  
  • Custom diagnostic mutation analysis (KM) is available to family members if mutations are identified by targeted mutation testing or sequencing analysis.
  • Prenatal testing is available only for known familial mutations to individuals who are confirmed carriers of mutations. Please contact the laboratory genetic counselor to discuss appropriate testing prior to collecting a prenatal specimen.
  • X-Linked Intellectual Disability panels are available for 30, 60, and 90 genes.

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