Ann Lab Med.  2024 Nov;44(6):625-627. 10.3343/alm.2024.0140.

A Family With Nail-Patella Syndrome Caused by a Germline Mosaic Deletion of LMX1B

• KMID: 2560817
• DOI: http://doi.org/10.3343/alm.2024.0140

Figure

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  Fig. 1 Plain radiographs of the knees of the proband in skyline (top) and lateral (bottom) views. (A) In 2016, neither patellae was visible. (B) In 2019, limited bilateral patellar ossification without demonstrable normal patella was visible. Images in both panels are suggestive of Nail-patella syndrome.

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  Fig. 2 Integrative Genomics Viewer snapshot of the family (A) and gap-PCR design and results (B–D). (A) Clockwise from top left: the proband (GL00285P), father (GL00285F), mother (GL00285M), and brother (GL00285S). The proband and her brother have right-clipped reads (red box) harboring the same breakpoint partially aligned to exon 4 of LMX1B. This right-clipped read is also observed for the proband’s mother (red box) but not the father. (B) Three 20-mer oligos were used to design a PCR assay for the detection of a deletion. EX-4F (purple arrow) is a common forward primer, and EX-4R and IVS-6R (red arrows) are reverse primers for wild-type detection and deletion confirmation, respectively. LMX1B consists of eight exons, with a DNA-binding domain spanning exons 4–6. Loss of this domain was predicted in this family. (C) A band of 648 bp, the amplicon of the EX4-F/IVS6-R primer pair, and a band of 489 bp, the product of the EX4-F/R primer pair, were identified in the proband (GL00285P), her brother (GL00285S), and their mother (GL00285M). Therefore, a deletion spanning exons 4–6 was confirmed. In the father (GL00285F), a 648-bp band was not observed, indicating no deletion. The negative control (NC) also did not have a 648-bp band. (D) The 648-bp PCR product was extracted and Sanger-sequenced. A breakpoint was identified between c.640 and c.887-555 in the electropherogram.

Reference

References

1. Marini M, Bocciardi R, Gimelli S, Di Duca M, Divizia MT, Baban A, et al. 2010; A spectrum of LMX1B mutations in Nail-Patella syndrome: New point mutations, deletion, and evidence of mosaicism in unaffected parents. Genet Med. 12:431–9. DOI: 10.1097/GIM.0b013e3181e21afa. PMID: 20531206.

2. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. 2015; Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 17:405–24. DOI: 10.1038/gim.2015.30. PMID: 25741868. PMCID: PMC4544753.

3. Riggs ER, Andersen EF, Cherry AM, Kantarci S, Kearney H, Patel A, et al. 2020; Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 22:245–57. DOI: 10.1038/s41436-019-0686-8. PMID: 31690835. PMCID: PMC7313390.

4. Seol J-H, Shim EY, Lee SE. 2018; Microhomology-mediated end joining: Good, bad and ugly. Mutat Res. 809:81–7. DOI: 10.1016/j.mrfmmm.2017.07.002. PMID: 28754468. PMCID: PMC6477918.

5. Yan X, Lin J, Wang Y, Xuan J, Yu P, Guo T, Jin F. 2019; A novel small deletion of LMX1B in a large Chinese family with nail-patella syndrome. BMC Med Genet. 20:DOI: 10.1186/s12881-019-0801-3. PMID: 31053111. PMCID: PMC6499979. PMID: 23a353489c1046babe7fe5e5d85b6a98.

6. Sato U, Kitanaka S, Sekine T, Takahashi S, Ashida A, Igarashi T. 2005; Functional Characterization of LMX1B Mutations Associated with Nail-Patella Syndrome. Pediatr Res. 57:783–8. DOI: 10.1203/01.PDR.0000157674.63621.2C. PMID: 15774843.

7. Gerasimavicius L, Livesey BJ, Marsh JA. 2022; Loss-of-function, gain-of-function and dominant-negative mutations have profoundly different effects on protein structure. Nat Commun. 13:DOI: 10.1038/s41467-022-31686-6. PMID: 35794153. PMCID: PMC9259657. PMID: 25ec647fd0494726b71c4fe1559ad371.

8. Bongers EMHF, De Wijs IJ, Marcelis C, Hoefsloot LH, Knoers NVAM. 2008; Identification of entire LMX1B gene deletions in nail patella syndrome: evidence for haploinsufficiency as the main pathogenic mechanism underlying dominant inheritance in man. Eur J Hum Genet. 16:1240–4. DOI: 10.1038/ejhg.2008.83. PMID: 18414507.

9. Xu N, Shi W, Cao X, Zhou X, Jin L, Huang H-F, et al. 2023; Parental mosaicism detection and preimplantation genetic testing in families with multiple transmissions of de novo mutations. J Med Genet. jmg-2022-108920:DOI: 10.1136/jmg-2022-108920. PMID: 36707240. PMCID: PMC10447385.

10. Campbell M, Ian , Stewart R, Jonathan , James A, Regis , Lupski R, James , Stankiewicz P, Olofsson P, Shaw A, Chad . 2014; Parent of Origin, Mosaicism, and Recurrence Risk: Probabilistic Modeling Explains the Broken Symmetry of Transmission Genetics. Am J Hum Genet. 95:345–59. DOI: 10.1016/j.ajhg.2014.08.010. PMID: 25242496. PMCID: PMC4185125.