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[ Diffuse Lung Disease CHEST Review ] 56

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Familial Pulmonary Fibrosis 61
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8 Genetic Features and Clinical Implications 63
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Q16Q1 David Zhang, MD; and Chad A. Newton, MD
11 Q2 66
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Pulmonary fibrosis comprises a wide range of fibrotic lung diseases with unknown pathogenesis
14 69
and poor prognosis. Familial pulmonary fibrosis (FPF) represents a unique subgroup of patients
15 70
16 in which at least one other relative is also affected. Patients with FPF exhibit a wide range of
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17 pulmonary fibrosis phenotypes, although idiopathic pulmonary fibrosis is the most common 72
18 subtype. Despite variable disease manifestations, patients with FPF experience worse survival 73
19 compared with their counterparts with the sporadic disease form. Therefore, ascertaining a 74
20 positive family history not only provides prognostic value but should also raise suspicion for the 75
21 inheritance of an underlying causative genetic variant within kindreds. By focusing on FPF 76
22 kindreds, rare variants within surfactant metabolism and telomere maintenance genes have 77
23 been discovered. However, such genetic variation is not solely restricted to FPF, as similar rare 78
24
variants are found in patients with seemingly sporadic pulmonary fibrosis, further supporting 79
25 80
the idea of genetic susceptibility underlying pulmonary fibrosis as a whole. Researchers are
26 81
beginning to show how the presence of rare variants may inform clinical management, such as
27 82
informing predisposition risk for yet unaffected relatives as well as informing prognosis and
28 83
29 therapeutic strategy for those already affected. Despite these advances, rare variants in sur-
84
30 factant and telomere-related genes only explain the genetic basis in about one-quarter of FPF 85
31 kindreds. Therefore, research is needed to identify the missing genetic contributors of pulmo- 86
32 nary fibrosis, which would not only improve our understanding of disease pathobiology but may 87
33 offer additional opportunities to improve the health of patients. CHEST 2021; -(-):--- 88
34 89
35 KEY WORDS: familial pulmonary fibrosis; genetics; surfactant; telomere Q6
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37 92
Pulmonary fibrosis is a heterogeneous group environmental insults and genetic
38 93
of chronic lung conditions marked by vulnerability confer disease susceptibility.
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aberrant inflammation and collagen Although sporadic forms of pulmonary
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41
deposition leading to progressive fibrosis are predominant, familial clustering 96
42 physiological impairment and death.1 The is relatively common. The recent explosion 97
43 inciting pathobiological events that lead to of genetics research has uncovered a host of 98
44 pulmonary fibrosis are largely unknown; risk variants implicating a variety of disease 99
45 however, it is believed that both pathways, the effects of which are most 100
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47 102
48 ABBREVIATIONS: CHP = chronic hypersensitivity pneumonitis; Critical Care Medicine, University of Texas Southwestern Medical 103
49 CTD = connective tissue disease; DC = dyskeratosis congenita; FPF = Center, Dallas, TX. 104
familial pulmonary fibrosis; IPF = idiopathic pulmonary fibrosis; ILD = FUNDING/SUPPORT: D. Z. receives support from The Stony Wold- Q4
50 interstitial lung disease; LTL = leukocyte telomere length; SNP = single 105
Herbert Fund. C. A. N. receives support from the National Institutes
51 nucleotide polymorphism; U-ILD = unclassifiable interstitial lung of Health, National Heart, Lung, and Blood Institute [K23HL148498]. 106
Q15
52 disease; VUS = variant of unknown significance CORRESPONDENCE TO: Chad A. Newton, MD; email: chad.newton@ 107
Q5
AFFILIATIONS: From the Department of Medicine (D. Zhang), Divi-
53 Q3 utsouthwestern.edu 108
sion of Pulmonary, Allergy and Critical Care Medicine, Columbia
54 Copyright Ó 2021 American College of Chest Physicians. Published by 109
University Irving Medical Center, New York, NY; and the Department Elsevier Inc. All rights reserved.
55 of Internal Medicine (C. A. Newton), Division of Pulmonary and 110
DOI: https://doi.org/10.1016/j.chest.2021.06.037

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111 relevant in the inherited forms of pulmonary fibrosis. Importance of Family History Ascertainment 166
112 167
Familial pulmonary fibrosis (FPF) is diagnosed when at By definition, family history ascertainment is required to
113 168
least two relatives within the same family develop confer the FPF designation. This process should include
114 169
pulmonary fibrosis. This phenomenon was initially a detailed assessment of each relative’s medical history
115 170
116 described more than a century ago.2 However, in the focusing primarily on FPF-associated pulmonary and 171
117 1950s and 1960s, clinicians began to astutely recognize extrapulmonary manifestations (Table 1). Age- 172
118 that FPF likely represented a unique version of fibrotic dependent onset of disease and reduced penetrance can 173
119 lung disease resulting from inherited determinants.3,4 sometimes obscure familial cases. In fact, symptomatic 174
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Despite the advanced diagnostic and therapeutic tools at pulmonary fibrosis often does not manifest until after 175
121
our disposal today, the diagnosis of FPF relies, almost the fifth decade of life, even in those with inherited 176
122
entirely, on detailed patient-clinician discussions, as it pathogenic rare variants.16 In addition, genetic 177
123 anticipation has been reported in FPF families wherein 178
124
did > 100 years ago. Accordingly, the current review 179
discusses the importance of family history ascertainment subsequent generations develop more severe disease at
125 180
and focuses on the clinical implications of the FPF an earlier age. Pedigree construction is a simple yet
126 181
entity. We outline syndromic features that suggest the methodical approach to assess for inherited forms of
127 182
presence of an underlying pathogenic rare variant and pulmonary fibrosis, which can be updated as new
128 183
129 discuss their clinical ramifications. One unique form of information is obtained from kindreds. 184
130 FPF, the Hermansky-Pudlak syndrome, was recently Patients with FPF can manifest a spectrum of 185
131 reviewed5 and therefore is not discussed here. Lastly, we 186
pulmonary fibrosis phenotypes. Although accurate
132 187
review the utility of genetic testing and provide a pulmonary fibrosis classification relies heavily on
133 188
prospective on how genetic information can be radiographic characterization, FPF cases often do not
134 189
135
leveraged in the clinical setting. conform to typical radiographic patterns,17 making 190
136 dogmatic etiology-based classification challenging. IPF is 191
137 Epidemiology of FPF the most common phenotype of patients with FPF9,18; 192
138 Defining the true prevalence of pulmonary fibrosis in the however, other subtypes commonly occur. Prior Q7
193
139
population is challenging. Epidemiologic studies multicenter cohort studies have shown that 20% to 194
140 25% of patients with IPF, as well as 14% to 17% of 195
estimate the prevalence of idiopathic pulmonary fibrosis
141 patients with chronic hypersensitivity pneumonitis 196
(IPF) at 13.4 to 18.5 per 100,000 people,6 which is orders
142 (CHP), 15% with unclassifiable interstitial lung disease 197
of magnitude larger than the estimated FPF prevalence
143 (U-ILD), and 3% to 8% with connective tissue disease- 198
144
of 1.3 to 5.9 per 1,000,000 people.7 In contrast, 199
observational cohort studies indicate that FPF may be ILD (CTD-ILD), have a family history of pulmonary
145 200
much more common, affecting up to 20% of patients fibrosis (Fig 1).19-21 Furthermore, even relatives within
146 201
147 with pulmonary fibrosis.8-10 This discordance likely 202
148 reflects differences in access to patient-level data for TABLE 1 ] Clinical Features That Increase Suspicion for 203
149 family history validation. Recent results from Familial Pulmonary Fibrosis Q14
204
150 prospective pulmonary fibrosis screening programs History of pulmonary fibrosis for any reason in one or 205
151 suggest that the prevalence of FPF is likely still more family members 206
152 Age of pulmonary fibrosis onset within family 207
underappreciated. Three independent groups used
153 Pediatric onset (age < 18 y) 208
radiographic screening for asymptomatic relatives of
154 209
patients with pulmonary fibrosis and identified Younger age of onset with each generation affected
155 (genetic anticipation) 210
subclinical disease in 15% to 31% of cases.11-13
156 211
Interestingly, Hunninghake et al13 found that 31% of Lung cancer and pulmonary fibrosis co-segregation
157 within kindred 212
158 asymptomatic relatives of patients with seemingly 213
Extrapulmonary manifestations
159 sporadic pulmonary fibrosis had radiographic interstitial 214
Bone marrow failure (eg, aplastic anemia,
160 lung abnormalities, which is four times higher than myelodysplastic syndrome) 215
161 community-dwelling adults.14,15 Together, these studies 216
Macrocytosis with or without anemia
162 confirm family history as a risk factor for pulmonary 217
Cryptogenic cirrhosis or portal hypertension
163 fibrosis in yet-unaffected relatives9 and show that the 218
164 Premature graying of the hair (by the third or fourth 219
burden of FPF may be much higher than previously decade of life)
165 220
suspected.

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221 276
222 Familial Pulmonary Fibrosis 277
223 Familial IPF (25%) 278
224 Sporadic IPF (75%) 279
225 280
226 281
227 CHP 282
(12%)
228 283
Familial CHP (15%)
229 284
Sporadic CHP (85%)
230 285
231 286
U-ILD
232 287
(20%)
233 IPF 288
234 (60%) 289
Familial U-ILD (15%)
235 Sporadic U-ILD (85%) 290
236 291
237 292
CTD
238 (8%) 293
239 294
print & web 4C=FPO

240 Familial CTD-ILD (5%) 295

241 Sporadic CTD-ILD (95%) 296
242 297
243 298
244 Figure 1 – Estimated makeup of clinical diagnoses of patients with familial pulmonary fibrosis. CHP ¼ chronic hypersensitivity pneumonitis; CTD ¼ Q13
299
connective tissue disease; IPF ¼ idiopathic pulmonary fibrosis; U-ILD ¼ unclassifiable interstitial lung disease. Q17
245 300
246 301
247 the same family can manifest different pulmonary counterparts with sporadic disease (Fig 2). In this study, 302
248 fibrosis subtypes.18,22 patients with familial IPF experienced an 80% higher 303
249 304
mortality risk than those with sporadic IPF, whereas
250 Although a positive family history may not inform the 305
patients with familial non-IPF had a 200% higher
251 clinical diagnosis, the presence of familial disease does 306
252 have prognostic value. Cutting et al21 found that patients mortality risk than their counterparts with sporadic 307
253 with a self-reported family history of pulmonary fibrosis disease. In addition, patients with FPF diagnoses that 308
254 experienced worse survival compared with their traditionally confer a better prognosis, such as CTD- 309
255 310
256 1.00 311
257 312
258 0.75 313
259 314
Survival

260 0.50 315

261 316
262 0.25 317
263 318
264
P < .01 319
0.00
265 320
0 2 4 6 8 10
266 321
Years
267 322
No. at risk
268 323
Sporadic IPF 400 230 89 39 14 6
269 Familial IPF 134 67 27 9 3 0 324
270 Sporadic non-IPF ILD 638 364 185 114 76 46 325
271 Familial non-IPF ILD 90 58 22 6 3 2 326
Figure 2 – Decreased survival in familial forms of pul-
272
Sporadic IPF Familial IPF monary fibrosis. IPF ¼ idiopathic pulmonary fibrosis; 327
273 ILD ¼ interstitial lung disease. (Reprinted from Cutting 328
Sporadic non-IPF ILD Familial non-IPF ILD
et al.21)
print & web 4C=FPO

274 329
275 330

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331 SFTPC and SFTPA1/2 exhibit autosomal dominant 386
ILD, had similar survival characteristics as patients with
332 inheritance, whereas inheritance of ABCA3 is autosomal 387
sporadic IPF. Therefore, the FPF designation represents
333 388
an easily identifiable supplement to the clinical recessive.43
334 389
335
pulmonary fibrosis diagnosis that signifies higher risk. Surfactant-related gene variants have diverse molecular 390
336 consequences depending on the gene and involved 391
337 FPF Genetic Variation domain. The most common risk variant in SFTPC, 392
338 Although a positive family history can provide broad encoding a missense mutation (I73T), causes altered 393
339 surfactant protein C trafficking and proteostasis.44 394
information regarding heritability and disease course,
340 395
identifying specific variants can improve predictive Damaging variants in the C-terminal BRICHOS domain
341 396
resolution. The known genetic variants that are of SFTPC, as well as damaging variants in SFTPA1/2,
342 397
343
associated with pulmonary fibrosis fall into two broad cause protein misfolding and endoplasmic reticulum
398
344 categories: common single nucleotide polymorphisms stress.45,46 Biallelic damaging variants in ABCA3 cause 399
345 (SNPs) and rare damaging variants. Common SNPs are reduced protein expression that disrupts surfactant 400
346 frequently found in the general population, defined by metabolism, resulting in epithelial cell toxicity.47,48 401
347 minor allele frequency > 5%. By contrast, rare damaging 402
From a clinical perspective, a unique hallmark of
348 variants are scarcely found in the general population, 403
families that harbor a rare surfactant-related gene
349 often with minor allele frequency < 0.1%. The frequency 404
350
variant is the variable age of disease onset within the 405
with which a variant is present in the population is
351 kindred, ranging from infancy to late adulthood. 406
inversely related to the size of its effect on disease risk,
352 Surfactant variant-related neonatal syndrome is typical 407
such that common SNPs confer a smaller effect size
353 for ABCA3 variant carriers but uncommonly occurs in 408
compared with that of rare variants.23 In this paradigm,
354 SFTPC variant carriers.42,49,50 From a pulmonary fibrosis 409
SNPs may contribute to disease risk but alone are
355 phenotypic standpoint, adults harboring surfactant- 410
356
insufficient to cause disease. In contrast, co-segregation 411
related variants have varied radiographic and histologic
357 of rare variants with disease is often found in FPF 412
patterns, including usual interstitial pneumonia,
358 kindreds with or without other risk factors, suggesting a 413
nonspecific interstitial pneumonia, and desquamative
359 causal relationship. 414
interstitial pneumonia.26,50,51 Rare pathogenic variants
360 415
To date, rare variants within two distinct biologic within SFTPA1 and SFTPA2 are associated with both
361 416
pathways have been implicated in adult-onset FPF: pulmonary fibrosis and lung adenocarcinoma.27,52
362 417
363
surfactant metabolism (SFTPC,24-26 SFTPA1/2,27 Although these variants are rare among FPF kindreds, Q8 418
364 ABCA328) and telomere maintenance (TERT,29,30 their presence should trigger diligent lung cancer 419
365 TERC,29,30 PARN,31,32 RTEL1,31,33,34 NAF1,35 DKC1,36,37 surveillance. Because surfactant production is limited to 420
366 TINF2,38 ZCCHC8,39 and NOP1040). Collectively, rare the lung, rare surfactant variants do not cause 421
367 variants in these genes are found in about 25% of extrapulmonary manifestations. The identification of a 422
368 patients with FPF and, when present, can inform rare surfactant-related variant in a proband can help 423
369 extrapulmonary manifestations, clinical course, and inform pulmonary fibrosis susceptibility in unaffected 424
370 management considerations. relatives who also inherited the rare variant, and 425
371 radiographic screening can identify subclinical disease in 426
372 427
Clinical Implications of Surfactant-Related Gene this at-risk group.53 However, given their low
373 Variants 428
prevalence, it is unclear if the natural history for
374 429
Genetic profiling of large kindreds led to the discovery of surfactant-related variants in adult-onset FPF differs
375 430
rare surfactant-related gene variants that predispose to from their sporadic counterparts.
376 431
377
adult-onset FPF. The most common surfactant gene 432
implicated in adult-onset FPF is SFTPC, which has been Clinical Implications of Telomere-Related Gene
378 433
found in 2% to 25% of patients with FPF, although the Variants
379 434
380 larger estimates are likely related to founder effects.25,41 Rare variants within telomere-related genes are found in 435
381 Conversely, rare variants in SFTPA1/2 are found in < about one-quarter of FPF kindreds, with variants in 436
382 1% of FPF cases. Rare biallelic variants in ABCA3 have TERT affecting 8% to 15% of all FPF.29,30,54 437
383 been described in FPF but more commonly present in Comparatively, PARN and RTEL1 variants each 438
384 infancy.28,42 The link between rare heterozygous variants comprise about 5% to 10% of FPF cases,31 followed by 439
385 440
and adult-onset FPF is less clear. Kindreds harboring TERC at 1% to 2%.54 Rare variants within DKC1, TINF2,

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441 NAF1, NOP10, and ZCCHC8 genes have been identified regarding possible telomeropathy manifestations and 496
442 in few families, and their suspected prevalence is < age of disease onset is critical. 497
443 498
1%.35,36,38-40 Telomeres comprise six-nucleotide repeats
444 Not only are the telomere-related gene variants 499
located at chromosomal ends that buffer against loss of
445 associated with varied extrapulmonary manifestations, 500
protein-encoding DNA during cellular replication.
446 but their pulmonary fibrosis subtypes are also 501
Collectively, the telomere-related genes serve to protect,
447 heterogeneous. Approximately one-half of rare 502
448
maintain, or elongate telomeres. Although telomere 503
telomere-related gene variant carriers develop IPF,
449 shortening is a normal function of aging, damaging 504
whereas others develop CHP (7%-12%), CTD-ILD (2%-
450 variants within these genes often result in pathologic 505
3%), U-ILD (8%-20%), and other idiopathic interstitial
451 shortening. The majority of telomere-related gene 506
pneumonias (14%-18%).22,54 Although the pulmonary
452 variant carriers have age-adjusted telomere lengths 507
fibrosis phenotype may be variable, rare telomere-
453 below the 10th percentile, although gene-specific 508
454
related gene variant carriers experience uniformly 509
differences may occur; PARN variants tend to cause less
455 progressive disease and poor survival.22 Similar 510
extreme telomere shortening than TERT, TERC, or
456 observations have been extended to those with sporadic 511
RTEL1 variants.22,31 Therefore, measurement of
457 forms of pulmonary fibrosis. Ley et al61 found that 512
leukocyte telomere length (LTL) alone may be an
458 patients with CHP and qualifying variants in TERT, 513
imprecise screening tool for the presence of a pathogenic
459 PARN, and RTEL1 experienced worse transplant-free 514
telomere-related gene variant.
460 survival compared with those without a variant. This 515
461 finding suggests that the genetic diagnosis may be more 516
Phenotypically, damaging variants in telomere-related
462 517
genes are associated with multisystem abnormalities prognostically informative than the specific pulmonary
463 518
collectively referred to as telomeropathies, or short fibrosis diagnosis.
464 519
telomere syndromes. The prototypic telomeropathy is
465 Patients with adult-onset sporadic pulmonary fibrosis 520
466
the pediatric disorder dyskeratosis congenita (DC), 521
are also enriched for rare telomere-related gene variants
467 which is often due to homozygous telomere-related gene 522
and short telomere length. Rare telomere-related gene
468 mutations and extreme telomere shortening. The classic 523
variants are present in about 10% of sporadic IPF, CHP,
469 manifestations of DC include abnormal skin 524
and rheumatoid arthritis-ILD cases.61-64 Although short
470 pigmentation, oral leukoplakia, and nail dystrophy; 525
age-adjusted telomere length is found in about one-half
471 however, bone marrow failure occurs in > 80% of DC 526
of patients with FPF,31,65 it is also present in sporadic
472 cases and is the leading cause of death.55 Pulmonary 527
473
disease in about 20% to 60% of IPF,66,67 20% to 35% of 528
fibrosis develops in approximately 20% of patients with
474 CHP,20 and 26% of rheumatoid arthritis-ILD.19 Not only 529
DC and often manifests in early adulthood or following
475 do short telomeres and pulmonary fibrosis coexist, but 530
bone marrow transplantation.56 In contrast, pulmonary
476 short telomere length is potentially causative of 531
fibrosis is the most common manifestation in adults
477 pulmonary fibrosis. Using a polygenic score of common 532
with heterozygous rare telomere-related gene variants,
478 SNPs associated with telomere length, Duckworth et al68 533
479
although extrapulmonary manifestations reminiscent of 534
used a Mendelian randomization strategy to show a
480 DC phenotypes can coexist within patients or relatives. 535
causal relationship between short telomere length and
481 Such manifestations include bone marrow dysfunction, 536
IPF but not COPD.
482 liver disease, predisposition to malignancy, and 537
483 premature hair graying.57 Importantly, relatives within Given this information, LTL has been evaluated as a 538
484 families harboring telomere-related gene variants may potentially informative biomarker, and multiple studies 539
485 manifest different telomeropathy disorders. For have shown that short LTL consistently informs 540
486 example, the proband may only have pulmonary fibrosis prognosis. Stuart et al69 reported that shorter LTL was 541
487 542
while their relatives have only bone marrow disease or associated with worse mortality in patients with IPF,
488 543
premature hair graying. In other cases, multiple which has since been replicated in multiple ethnically
489 544
telomeropathy features can manifest within a single diverse IPF cohorts.64,70,71 Short LTL is similarly
490 545
individual. In addition, short telomere length itself is a prognostic for other forms of pulmonary fibrosis,
491 546
492
heritable trait passed from generation to generation,16,58 including CHP20,72 and U-ILD.73 Although 547
493 mediating genetic anticipation in which more severe extrapulmonary telomeropathy manifestations may 548
494 disease phenotypes present at younger ages.22,59,60 For contribute to their poor survival, patients with short LTL 549
495 these reasons, obtaining a detailed family history experience rapid lung function decline, indicating that 550

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551 progressive lung fibrosis is a key contributor to their a portion of the missing heritability may be due to the 606
552 mortality.19,64 additive or multiplicative effects of many variants, 607
553 608
including both rare variants and common SNPs, rather
554 Interactions between medical therapies and telomere 609
than a single perturbation. Advancements in sequencing
555 dysfunction may also influence clinical outcomes. We 610
depth and analytic strategies may allow researchers to
556 reported that patients with IPF and LTL below the 10th 611
quantitate polygenic interactions, accounting for the
557 percentile disproportionally experienced worse 612
558
differential risk of both common SNPs and rare variants. 613
outcomes when exposed to immunosuppressive
559 Fourth, epigenetic sources of heritability may explain a 614
medications.66 Although immunosuppression is no
560 portion of disease risk. One source of epigenetic- 615
longer used for IPF, it remains the mainstay for many
561 mediated inheritance is telomere length itself, which is a 616
non-IPF forms of pulmonary fibrosis in which short
562 heritable trait independent of telomere-related variant 617
LTL and telomere-related gene mutations are prevalent.
563 inheritance29,76 and may alone explain a subset of the 618
564
Adegunsoye et al72 recently showed that mycophenolate 619
patients with FPF. Finally, shared environmental
565 therapy was associated with a mortality benefit for 620
exposures may also contribute to the development of
566 patients with CHP and longer LTL, which was absent in 621
FPF. Small case series have described familial or
567 those with short LTL. Together, these studies suggest 622
community clusters of CHP through shared exposure to
568 that the short LTL-immunosuppression interaction 623
an occult antigen.77-79 However, given the prevalence of
569 confers a phenotype-specific effect ranging from not 624
risk gene mutations in CHP, it remains likely that shared
570 beneficial to potentially harmful. The relative influence 625
571
exposures and underlying genetic susceptibility both 626
of telomere dysfunction within disease subtypes may
572 contribute to these cases. 627
partially explain these results; however, additional
573 628
research is needed to understand the pathobiology
574 Clinical Genetic Testing Considerations 629
underlying this potential interaction. Because the
575 630
majority of patients with short LTL or rare variants in As the framework of FPF genetic heritability becomes
576 631
577
telomere-related genes either exhibit IPF or non-IPF clearer, clinicians should consider how genetic testing 632
578 progressive fibrotic interstitial lung disease, the use of can be leveraged in patient care. Genomics-based testing 633
579 antifibrotic therapies remains a safe and seemingly options include genetic sequencing and telomere length 634
580 effective option to slow lung function decline.64,74 measurement. Genetic sequencing aims to identify 635
581 specific variants within risk genes. This can be 636
582 accomplished via whole genome, whole exome, or panel 637
Heritability Gap in Familial Pulmonary
583 sequencing in which only previously identified risk 638
Fibrosis
584 genes are assessed. In the correct clinical context (strong 639
585 Causative rare genetic variants have been discovered in a 640
family history with syndromic manifestations), the rate
586 subset of FPF kindreds, largely explaining the genetic 641
of identification of a pathogenic or likely pathogenic
587 risk within those families. In addition, common SNPs 642
variant in a known risk gene can be relatively high.
588 such as the MUC5B rs35705950 SNP, which was 643
Conversely, telomere length can be measured within
589 originally identified through family-based linkage scans, 644
590
peripheral blood leukocytes, and age-adjusted values are 645
also likely contribute to FPF risk.75 However, a large
591 returned to the clinician and patient. Telomere length 646
portion of FPF kindreds remain without a predominant
592 testing does not provide information about a specific 647
genetic diagnosis. This heritability gap may be
593 gene or mutation, as short telomere length can occur 648
attributable to numerous causes. First, there are
594 independent of rare variants in telomere-related genes. 649
limitations to accurately predicting the pathogenic
595 Considerations of which test to perform depend on the 650
effects of any one specific variant. This is especially true
596 pretest probability of an FPF genetic syndrome. For 651
597
for variants that lie within noncoding regions of the 652
those with telomeropathy manifestations, telomere
598 genome as well as silent, or synonymous, variants 653
length measurement or genetic sequencing can be
599 without a predicted amino acid change. Such variants 654
performed simultaneously or in series, as these tests
600 often elude typical genetic screens and require in-depth 655
provide different, yet complementary information.
601 functional analyses for identification. Second, due to the 656
Those with clinical features of a surfactant-related
602 limited sample sizes of previously costly next-generation 657
603
variant should undergo genetic sequencing only. 658
sequencing studies, discovery has been saturated with
604 large effect risk genes; future studies aiming to identify Although genetic testing is available, the risks and 659
605 660
novel risk genes may require much larger cohorts. Third, benefits of testing should be considered prior to

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661 embarking on this endeavor. Patients with a suggestive hematologic abnormalities, or oral leukoplakia (a 716
662 family history should undergo pretest counseling to precursor to squamous cell carcinoma). Due to the 717
663 718
better understand the shortcomings and potential progressive nature of pulmonary fibrosis in patients with
664 719
consequences of genetic testing. First, sequencing results telomeropathy, early referral for lung transplant may be
665 720
are often neither positive nor negative; instead, considered. However, small studies have suggested that
666 721
sequencing commonly reveals variants of unknown these patients are at risk for bone marrow abnormalities,
667 722
668
significance (VUS). Adjunctive testing, such as clinical infections, and allograft dysfunction.81-83 Additional 723
669 telomere length measurement in the case of a telomere- studies are needed to outline optimal strategies for 724
670 related gene VUS, may help assess variant pathogenicity. posttransplant management. For those with SFTPA1/2 725
671 Expansion of genetic testing in relatives, a process variants, screening for lung cancer should be performed. 726
672 known as cascade testing, may be informative if the The identification of a rare variant in a proband also has 727
673 suspicious VUS co-segregates with disease, thus ramifications for their relatives who may have inherited 728
674 providing suggestive evidence of variant pathogenicity. the variant. Therefore, relatives may opt to undergo 729
675 In addition, it is possible that some patients who have a genetic sequencing to improve risk stratification. Those 730
676 731
negative genetic test result may harbor yet-to-be- relatives who are found to harbor the variant should be
677 732
identified variants that predispose to disease. Second, the counseled to avoid potential fibrogenic exposures and
678 733
cost of genetic testing can be substantial and is often undergo monitoring for development of clinical disease.
679 734
deferred to the patient. Third, genetic testing itself may In essence, relatives of FPF probands become patients in
680 735
681
have a psychological impact on patients and their their own right. 736
682 relatives. This impact may not always be negative, and in 737
Despite the growing recognition of genetic variants
683 fact some patients may be relieved by knowing their 738
underlying FPF, genetic testing may not identify a
684 genetic status. Encouragingly, Carmichael et al80 found 739
causative rare variant in a known risk gene in up to
685 that relatives of patients with pulmonary fibrosis who 740
75% of FPF kindreds. Although a “negative” result may
686 underwent clinical and genetic screening did not 741
687
seem reassuring, these patients should still be considered 742
experience excessive decisional regret, but there are still
688 at risk for developing disease and require close 743
many unknowns about the potential psychological
689 monitoring with radiographic and physiological 744
ramifications of genetic testing that require exploration.
690 screening.11-13 In some cases, future re-assessment may 745
Given the nuances and potential pitfalls of genetic
691 be considered as new genetic discoveries are made, 746
testing, we recommend referring patients with FPF to
692 potentially resolving undiagnosed cases. If screening 747
certified genetic counselors who can offer invaluable
693 identifies subclinical disease, early initiation of 748
694
insight through pretesting counseling, choosing the 749
antifibrotic therapy should be considered when
695 appropriate genetic test, interpreting the results, and 750
symptoms develop or with any evidence of progression.
696 providing posttesting counseling to patients and their 751
Early recognition of disease offers a substantial
697 relatives. 752
opportunity to delay further disease progression and
698 753
improve clinical outcomes in FPF kindreds.
699 754
700 Prospect of Genetics-Informed FPF 755
701 Management Conclusions 756
702 757
The idea of precision medicine in pulmonary fibrosis Patients with FPF represent a uniquely vulnerable
703 758
leans heavily on genetics-informed decision-making. population. Their disease carries a high risk for
704 759
This is already being realized for the roughly 25% of FPF mortality, manifests with atypical radiographic or
705 760
kindreds who harbor a rare variant in a risk gene, paving histologic features, and poses challenging questions for
706 761
707
the way for patient and family-specific approaches to their relatives. However, major advances in pulmonary 762
708 management. For instance, the presence of a rare fibrosis genetics have yielded a much greater 763
709 telomere-related variant might sway the clinician and understanding of the genetic architecture that informs 764
710 patient away from performing invasive diagnostic these unique characteristics. Over the last few decades, 765
711 biopsies because the genetic abnormality informs disease around one-quarter of the heritability of FPF has been 766
712 course more than the specific pulmonary fibrosis explained, which is no trivial task for a disease with such 767
713 subtype.22 Furthermore, the presence of a rare telomere- extreme phenotypic heterogeneity. FPF is becoming 768
714 related variant should trigger additional evaluations for increasingly recognized, offering substantial 769
715 770
extrapulmonary disorders such as occult cirrhosis, opportunities to decipher the remaining sources of

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771 heritability and unlock novel pathways that contribute 16. Diaz de Leon A, Cronkhite JT, Katzenstein AL, et al. Telomere 826
772 lengths, pulmonary fibrosis and telomerase (TERT) mutations. PLoS 827
to lung fibrosis. With the pace of discovery over the past One. 2010;5:e10680.
773 828
decade, the future of FPF diagnostics and management 17. Lee HY, Seo JB, Steele MP, et al. High-resolution CT scan findings in
774 familial interstitial pneumonia do not conform to those of idiopathic 829
has never been brighter.
775 interstitial pneumonia. Chest. 2012;142:1577-1583. 830
776 18. Steele MP, Speer MC, Loyd JE, et al. Clinical and pathologic features 831
Acknowledgments of familial interstitial pneumonia. Am J Respir Crit Care Med.
777
Q9 2005;172:1146-1152. 832
Financial/nonfinancial disclosures: The authors have reported to
778 CHEST the following: C. A. N. reports consulting fees from Boehringer 833
19. Newton CA, Oldham JM, Ley B, et al. Telomere length and genetic
779 Ingelheim. None declared (D. Z.). variant associations with interstitial lung disease progression and 834
780
Q10 Role of sponsors: The sponsor had no role in the design of the study, survival. Eur Respir J. 2019;53. 835
781 the collection and analysis of the data, or the preparation of the 20. Ley B, Newton CA, Arnould I, et al. The MUC5B promoter 836
manuscript. polymorphism and telomere length in patients with chronic
782 hypersensitivity pneumonitis: an observational cohort-control study. 837
Q11
783 Other contributions: The authors thank the patients and families who Lancet Respir Med. 2017;5:639-647. 838
have generously participated in pulmonary fibrosis research endeavors.
784 They also thank Christine Kim Garcia, MD, PhD (Department of 21. Cutting C, Bowman WS, Dao N, et al. Family history of pulmonary 839
fibrosis predicts worse survival in patients with interstitial lung
785 Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, 840
disease. Chest. 2021;159(5):1913-1921.
786 Columbia University), for her mentorship, insights, and support of this 841
work. 22. Newton CA, Batra K, Torrealba J, et al. Telomere-related lung
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