ClinGen Dosage Sensitivity Curation Page

FMR1

  • Curation Status: Complete

Location Information

Select assembly: (NC_000023.10) (NC_000023.11)
Evidence for haploinsufficiency phenotype
PubMed ID Description
1642231 Wohrle et al (1992) describes a male born to healthy non consanguineous parents presenting with global developmental delay including speech delay. Height and weight was within normal range, stature was tall with rounded shoulders. The face was course with a long jaw and high wide forehead. Ears are large and testicle size was above the 90th percentile. Proband?s younger sister was described as healthy. Cytogenetics revealed a normal male karyotype. Southern blot analysis performed to detect amplification of the CGG repeats of the FMR1 gene revealed a deletion of the CGG repeat sequence. RFLP studies of the proband, proband?s mother, and proband?s sister identified the deletion observed in the proband to be de novo. Pulse field gel (PFG) electrophoresis and PCR estimated the deletion to be less than 250-kb in size extending from ~185-kb upstream of FMR1 (DXS548 marker) to intron 3 of FMR1. No additional genes are included in this deletion.
7670500 Lugenbeel et al (1995) describes two unrelated males with features ?highly suggestive of Fragile X syndrome?. Chromosomes were normal (46,XY) and FMR1 CGG repeat analysis by Southern blot analysis was within normal limits for both subjects. FMR1 protein expression was negative for both subjects interrogated by Western blot analysis. Subject 1 was identified to have a single nucleotide (frameshift) deletion in exon 5. Analysis of subject 1?s mother revealed that the frameshift deletion was de novo. Subject 2 was determined to have a two nucleotide missense change leading to aberrant splicing and premature termination. This variant was observed to be inherited from subject 2?s mildly affected mother. Subject 2?s half-sister, maternal aunt, and maternal grandmother were determined to be non-carriers of the two nucleotide deletion.
8069307 Meljer et al (1994) describes a three-generation family. Within this family 4 males and 2 females presented with characteristic Fragile X phenotype (all related). All affected males (patients 14, 15, 23, and 24-proband) and three phenotypically normal obligate carrier females (patients 3, 6, and 7) were identified to harbor a 1.6-kb deletion (ChrX:146,991,883-146,993,569)which includes FMR1-AS1, a long non-coding RNA and a portion of the 5?UTR of FMR1. The deletion was not observed in three unaffected males (patients 5, 12, and 13). Of note, patient 12 was not related to the family. Based on the pedigree it was suspected that the deletion was inherited from the deceased maternal grandfather (patient 2) of the male proband (patient 24). The deceased maternal grandfather (patient 24) was retrospectively concluded to have a normal appearance, intelligence, and behavior. It was suspected that the maternal grandfather was a germline mosaic for the 1.6-kb deletion. FMR1 mRNA expression was absent in all four affected males (patients 14, 15, 23, and 24-proband). FMR1 mRNA expression was present in normal controls and absent in two CGG expanded positive controls. It?s unclear if family members 1, 17, 18, 19, 20, and 21 are negative for the deletion or were not tested.

Haploinsufficiency phenotype comments:

While the expansion of the CGG trinucleotide repeat located in the 5-prime untranslated region of the FMR1 gene is the most common mechanism for fragile X syndrome, other loss of function FMR1 variants (as presented here) are also causative. PMID 22890812: Nagamani et al (2012) describes a male (subject 3) presenting with motor and language delay, macrocephaly, epicanthus inversus, and bilateral trigones of the lateral ventricles. Fragile X syndrome testing was performed, but results were not obtained. Array CGH identified a hemizygous 265.8-kb copy number loss (ChrX: 146,919,582?147,185,432; hg19) which includes FMR1, FMR1-AS1, a long non-coding RNA, and FMR1NB. The deletion was determined to be de novo. PMID 7530551: Gu et al (1994) describes a male with phenotypic features of Fragile X syndrome who harbors a <100-kb de novo deletion which extends from 80-kb upstream of the promoter to intron 7 of FMR1. PMID 9375726: Hammond et al (1997) describes a male with developmental delay harboring a de novo 300~400-kb intragenic deletion of FMR1. Mosaicism was not observed. Although the proband?s non-affected mother did not harbor the deletion she did have a full FMR1 mutation (completely methylated) with 700-900 CGG repeats. PMID 7943018: Trottier et al (1994) describes a male with a typical Fragile X phenotype with a ~130-kb deletion of the FMR1 gene that extends from 70-100-kb upstream of the promoter to within FMR1 (possibly extending to exon 9). It is unknown if the deletion was inherited or de novo. PMID 7825604: Hirst et al (1995) describes two unrelated males with developmental delay. Subject 1 presented with nocturnal epileiform seizures and learning and behavioral difficulties and was found to have a mosaic, de novo 660-bp deletion that encompassed the promoter region of FMR1. Subject 2 presented with ?typical Fragile X phenotype? and was found to have a de novo deletion that extends proximal to FMR1 and to intron 10 of FMR1. It?s unclear where the breakpoint upstream of FMR1 is located and if the deletion includes additional genes upstream of FMR1. Expression studies determined that no FMR1 mRNA was transcribed. PMID 1302032: Gedeon et al (1992) identified a ~2.5-Mb deletion which includes FMR1 and possibly FMR2 in a male patient with typical features of Fragile X syndrome. PMID 8281165: Tarleton et al (1993) identified a 3-Mb deletion, which includes FMR1 and possibly FMR2 and IDS in a male patient with typical features of Fragile X syndrome. PMID 7726157: Quan et al (1995) identified a maternally inherited >9-Mb deletion in a male patient. The deletion includes FMR1 and adjacent genes. PMID 18412117: Coffee et al (2008) provides a nice review of the literature regarding deletions of FMR1 in patients presenting with clinical features of Fragile X syndrome.

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

Triplosensitivity phenotype comment:

PMID 22549406: Vengoechea et al (2012) describes a male presenting with developmental delay, fine motor and speech delay, progressive seizures, and hyperactivity. Southern blot and PCR analysis for fragile X syndrome was normal. However, array CGH identified a de novo 86-kb copy number gain at Xq27.3 which included the entire FMR1 gene and FMR1-AS. A 363-kb copy number gain at 1q44 and a 169-kb copy number loss at 4p15.31 were also observed. The copy number variants at 1q44 and 4p15.31 were determined to be inherited from the unaffected father. Neither of the three copy number variants detected in the proband was observed in the mother. FMR1 mRNA expression levels of the proband were found to be within normal limits by RT-PCR. PMID 22890812: Nagamani et al (2012) describes two unrelated females presenting with developmental and language delay. Growth parameters were normal and there was no characteristic facial gestalt observed. Array CGH identified a 363-kb copy number gain in Subject 1 and a 348-kb copy number gain in Subject 2. Both duplications included the entire FMR1 gene. X-chromosome inactivation studies showed random X inactivation for both patients. PMID 19844254: Rio et al (2010) describes a family with three male members presenting with similar clinical findings of mild mental delay, hypogonadism, and short stature. All three individuals had IUGR, failure to thrive, mild learning difficulties, good verbal skills, undescended testis, small hands and feet, high-pitched voice, and mild dysmorphic features. Based on the pedigree the features observed were consistent with an X-linked recessive disorder. All three probands revealed to have a stable expansion of the FMR1 CGG repeat without abnormal methylation. Linkage analysis was performed on the three affected males and the three obligate carrier females. Array-CGH identified a 5.1-Mb duplication on Xq27.3q28 which was present in all three affected males and the three obligate carrier females. The X-inactivation profile of one of the obligate carriers showed completely skewed inactivation with 100% of the cells inactivating the duplicated X chromosomes. The remaining two obligate carrier females had random X-inactivation profiles (60/40 and 70/30). All three obligate carrier females were noted to not have learning difficulties, but did present with short stature and early menopause between the ages of 39 and 40. The Xq27.3q28 duplication identified encompassed 28 genes including FMR1. PMID 23897859: Hickey et al (2013) describes a male (previously described by Vasquez et al, 1979, PMID: 758423) reported to have hypotonia, seizures, feeding difficulties, thoracic hemivertebrae, short stature, microcephaly, obesity, and gross developmental delay. Southern blot and PCR analysis for fragile X syndrome was normal. Array CGH identified an 8-Mb duplication on Xq27.3q28. The duplication encompasses many genes including FMR1.

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.